Diamino heterocyclic carboxamide compound

ABSTRACT

Provided is a compound useful as an inhibitor against the kinase activity of EML4-ALK fusion protein. 
     As a result of intensive and extensive studies on compounds having inhibitory activity against the kinase activity of EML4-ALK fusion protein, the present inventors found that the diamino heterocyclic carboxamide compounds of the present invention had inhibitory activity against the kinase activity of EML4-ALK fusion protein. By this finding, the present invention was completed. The compounds of the present invention can be used as a pharmaceutical composition for preventing and/or treating cancer, such as lung cancer, non-small cell lung cancer, and small cell lung cancer.

This application is the U.S. national phase of International ApplicationNo. PCT/JP2010/057751 filed 6 May 2010 which designated the U.S. andclaims priority to JP Patent Application No. 2009-113936 filed 8 May2009, the entire contents of each of which are hereby incorporated byreference.

TECHNICAL FIELD

The present invention relates to diamino heterocyclic carboxamidecompounds useful as active ingredients in pharmaceutical compositions,particularly pharmaceutical compositions for cancer therapy.

BACKGROUND ART

Lung cancer is caused by disordered growth of tracheal, bronchial and/oralveolar cells as a result of losing their normal functions. The numberof people who die of lung cancer is the largest of the total of cancerdeaths (17%), and worldwide about 1.3 million people die of lung cancereach year.

Treatment for lung cancer is divided into three major categories:surgical operation (surgical therapy), anticancer agent (chemotherapy)and radioactive irradiation (radiation therapy), but the effectivenessof treatment will vary depending on the tissue type of lung cancer. Forexample, although a definite diagnosis of lung cancer is made by apathologist based on his cytohistopathological diagnosis on a microscopespecimen, small cell lung cancer, which constitutes about 20% of lungcancer cases, has often reached an advanced stage at the time ofdiscovery because it generally has a high grade of malignancy and willrapidly grow and spread and will often metastasize to other organs. Forthis reason, chemotherapy and/or radiation therapy is often used fortreatment of this cancer, but the prognosis is poor because small celllung cancer will often recur although it is relatively sensitive tothese therapies. On the other hand, in the case of non-small cell lungcancer, which constitutes the remainder of about 80%, surgical therapyis considered for use until a certain stage, but there is littleopportunity to use surgical operation in the subsequent stages wherechemotherapy and/or radiation therapy is mainly used for treatment.

Thus, in either type of lung cancer, chemotherapy is an important optionfor treatment.

ALK (Anaplastic Lymphoma Kinase) is a receptor tyrosine kinase and is aprotein having a transmembrane region in the middle part, flanked by atyrosine kinase region on the carboxyl-terminal side and anextracellular region on the amino-terminal side. It has previously beenreported that full-length ALK is expressed in several types of cancercells of ectodermal origin (e.g., neuroblastoma, glioblastoma, breastcancer, melanoma) (Non-patent Document 1). In some cases of humanmalignant lymphoma, it has also been reported that the ALK gene is fusedwith another gene (e.g., NPM gene, CLTCL gene, TFG gene, TPM3 gene, ATICgene, and TPM4 gene) as a result of chromosomal translocation, andthereby produces an oncogenic fusion tyrosine kinase (Science, vol. 263,p. 1281, 1994; Blood, vol. 86, p. 1954, 1995; Blood, vol. 95, p. 3204,2000; Blood, vol. 94, p. 3265, 1999; Oncogene, vol. 20, p. 5623, 2001).Also in the case of inflammatory myofibroblastic tumor, it is known thatthe ALK gene is fused with another gene (e.g., CARS gene, SEC31L1 gene,and RanBP2 gene) as a result of chromosomal translocation, and therebyproduces a fusion tyrosine kinase (Laboratory Investigation, a journalof technical methods and pathology, vol. 83, p. 1255, 2003;International Journal of Cancer, vol. 118, p. 1181, 2006; MedicinalResearch Reviews, vol. 28, p. 372, 2008). Most of partner molecules tobe fused with ALK have a complex-forming domain, and the generatedfusion products per se also appear to form complexes. This complexformation would induce uncontrol of ALK tyrosine kinase activity andabnormal activation of intracellular signals, thereby causingcanceration (Cellular and Molecular Life Science, vol. 61, p. 2939,2004; Nature Reviews Cancer, vol. 8, p. 11, 2008).

Moreover, recent reports have indicated the presence of a TPM4-ALKfusion protein in esophageal cancer by proteomics analysis procedures(World Journal of Gastroenterology, vol. 12, p. 7104, 2006; Journal ofMolecular Medicine, vol. 85, p. 863, 2007). Further, a fusion genebetween EML4 (echinoderm microtubule associated protein like-4) and ALKwas confirmed in specimens from lung cancer patients, and it was alsoreported that this EML4-ALK fusion gene has tumorgenicity and is acausal gene of cancer, and that inhibitors against its kinase activitysuppress the growth of various cells where the EML4-ALK fusion proteinis expressed (Patent Document 1 and Non-patent Document 2). Thesedocuments further show that inhibitors of the EML4-ALK fusion proteinare useful as therapeutic agents for lung cancer in EML4-ALKpolynucleotide-positive lung cancer patients. Further, in lung cancer,the presence of many variants of EML4-ALK has been proved (PatentDocument 1; Annals of surgical oncology, vol. 17, p. 889, 2010;Molecular Cancer Research, vol. 7, p. 1466, 2009; Clinical CancerResearch, vol. 15, p. 3143, 2009; Cancer, vol. 115, p. 1723, 2009;Clinical Cancer Research, vol. 14, p. 6618, 2008; Clinical CancerResearch, vol. 14, p. 4275, 2008), and the presence of TFG-ALK (Cell,vol. 131, p. 1190, 2007) and KIF5B-ALK (Clinical Cancer Research, vol.15, p. 3143, 2009) has been reported. Furthermore, it is known thatthere have been cases in which EML4-ALK is expressed in lung cancerpatients as well as colon cancer patients and breast cancer patients(Molecular Cancer Research, vol. 7, p. 1466, 2009).

Moreover, Patent Document 1 shows the following compounds A to D (eachbeing known as an ALK inhibitor) as examples of compounds havinginhibitory activity against the EML4-ALK fusion protein, and it alsodiscloses the actual values of their inhibitory activity against theEML4-ALK fusion protein. However, there is no specific disclosure aboutthe diamino heterocyclic carboxamide compounds according to the presentinvention.

Their respective chemical names are:4-[(3′-bromo-4′-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline (alsocalled WHI-P154) for compound A;N-[2-(3-chlorophenyl)ethyl]-2-[({[4-(trifluoromethoxy)phenoxy]acetyl}amino)methyl]-1,3-thiazole-4-carboxamidefor compound B;5-chloro-N⁴-[2-(isopropylsulfonyl)phenyl]-N²-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine(also called TAE684) for compound C; and2-[(5-bromo-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)amino]-N-methylbenzenesulfonamidefor compound D.

Moreover, in ALK fusion protein-expressing lymphoma cells, a compoundhaving ALK inhibitory activity, WHI-P154 (compound A shown above), hasbeen reported to inhibit cell growth and induce apoptosis (Non-patentDocument 3). However, there is no specific disclosure about the diaminoheterocyclic carboxamide compounds according to the present invention.

Likewise, TAE684 (compound C shown above) is known as an inhibitor of afusion protein from a fusion gene between NPM gene and ALK gene.

TAE684 structurally differs from the compounds of the present inventionin that the center ring sandwiched between two —NH groups is achloro-substituted pyrimidine ring.

Moreover, TAE684 has been reported to inhibit the spread of anaplasticlarge cell lymphoma (ALCL) by its inhibitory activity against theNPM-ALK fusion protein (Non-patent Document 4). On the other hand,although it is described that compounds including TAE684 have inhibitoryactivity against focal adhesion kinase (FAK) and are thereby useful forpreventing and/or treating non-small cell lung cancer and small celllung cancer, there is no information about actual therapeutic effects onthese lung cancers (Patent Document 2). Furthermore, there is nospecific disclosure about the diamino heterocyclic carboxamide compoundsaccording to the present invention.

Further reports were issued showing that ELM4-ALK is expressed innon-small cell lung cancer cells (NCI-H2228), that TFG-ALK is expressedin non-small cell lung cancer patients, and that TAE684 inhibits thegrowth of non-small cell lung cancer cells (NCI-H2228) (Patent Document1 and Non-patent Documents 5 and 6).

Further, it is reported that the compound below has Syk inhibitoryactivity and is useful as an active ingredient in agents for preventingor treating a disease in which Syk is involved, such as allergy,inflammation, immune disease, thrombus, and cancer (Patent Document 3).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention. Furthermore,the inhibitory activity against the kinase activity of EML4-ALK fusionprotein is neither disclosed nor suggested, and there is no specificdisclosure about therapeutic effects on cancer.

Further, it is reported that the compound below has inhibitory activityagainst protein kinase C and is useful as an active ingredient in agentsfor preventing or treating a disease in which protein kinase C isinvolved, such as diabetic complication, ischemia, inflammation, andcancer (Patent Document 4).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention. Furthermore,the inhibitory activity against the kinase activity of EML4-ALK fusionprotein is neither disclosed nor suggested, and there is no specificdisclosure about therapeutic effects on cancer.

Further, it is reported that the compound below has inhibitory activityagainst the kinase activity of EML4-ALK fusion protein and mutant EGFRprotein and is useful as an active ingredient in therapeutic agents forcancer including lung cancer, etc (Patent Document 5).

(In the formula, —X— is 1,3,5-triazine-2,4-diyl or quinazoline-2,4-diylwhich may be substituted. For other symbols in the formula, refer to thepublication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention.

Further, it is reported that the compound below has inhibitory activityagainst various kinases including ALK and is useful for treating cellproliferative disease (Patent Document 6).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention.

Further, it is reported that the compound below has inhibitory activityagainst ALK and/or c-Met and is useful for treating proliferativedisease (Patent Document 7).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention.

Further, it is reported that the compound below has inhibitory activityagainst various kinases including ALK and is useful for treatinghyperproliferative disease and angiogenic disease (Patent Document 8).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention.

Further, it is reported that the compound below has inhibitory activityagainst various kinases including IGF-1R and ALK and is useful fortreating cancer (Patent Document 9).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention.

Further, it is reported that the compound below has Syk inhibitoryactivity and is useful for treating allergy, autoimmune disease, cancer,and abnormal myeloid cell growth (Patent Document 10).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention. Furthermore,the inhibitory activity against the kinase activity of EML4-ALK fusionprotein is neither disclosed nor suggested, and there is no specificdisclosure about therapeutic effects on cancer.

Further, it is reported that the compound below has inhibitory activityagainst Aurora-B kinase and is useful for treating cancer, infectiousdisease, inflammation, and autoimmune disease (Patent Document 11).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention. Furthermore,the inhibitory activity against the kinase activity of EML4-ALK fusionprotein is neither disclosed nor suggested.

Further, it is reported that the compound below has STATE activationinhibitory activity and Th2 cell differentiation inhibitory activity andis useful for treating respiratory disease, asthma, and chronicobstructive pulmonary disease (Patent Document 12).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention. Furthermore,the inhibitory activity against the kinase activity of EML4-ALK fusionprotein is neither disclosed nor suggested, and there is no specificdisclosure about therapeutic effects on cancer.

Further, it is reported that the compound below has PKC inhibitoryactivity and is useful for treating allergy, inflammation, diabetes,cancer and the like (Patent Document 13).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention. Furthermore,the inhibitory activity against the kinase activity of EML4-ALK fusionprotein is neither disclosed nor suggested, and there is no specificdisclosure about therapeutic effects on cancer.

Further, it is reported that the compound below has inhibitory activityagainst PLK-1 and PLK-3 and is useful for treating cancer, cellproliferative disease, virus infection disease, autoimmune disease, andneurodegenerative disease (Patent Document 14).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention. Furthermore,the inhibitory activity against the kinase activity of EML4-ALK fusionprotein is neither disclosed nor suggested.

Further, it is reported that the compound below has HSP-90 inhibitoryactivity and is useful for treating cell proliferative disease, cancer,inflammation, arthritis, and angiogenic disease (Patent Document 15).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention. Furthermore,the inhibitory activity against the kinase activity of EML44-ALK fusionprotein is neither disclosed nor suggested.

Further, it is reported that the compound below has ALK, c-Met and Mps1kinase inhibitory activity and is useful for treating hyperproliferativedisease, cancer, and angiogenic disease (Patent Document 16).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention.

Further, it is reported that the compound below has inhibitory activityagainst Syk and Jak and is useful for treating heart disease,inflammation, autoimmune disease, and cell proliferative disease (PatentDocument 17).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention. Furthermore,the inhibitory activity against the kinase activity of EML4-ALK fusionprotein is neither disclosed nor suggested.

Further, it is reported that the compound below has IKK inhibitoryactivity and is useful for treating inflammation, immunopathy, cancer,neurodegenerative disease, age-related disease, heart disease, anddysbolism (Patent Document 18).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention. Furthermore,the inhibitory activity against the kinase activity of EML4-ALK fusionprotein is neither disclosed nor suggested.

Further, it is reported that the compound below has inhibitory activityagainst various kinases including ALK and is useful for treating cellproliferative disease and cancer (Patent Document 19).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention.

Further, it is reported that the compound below has ALK, ROS, IGF-1R andInsR kinase inhibitory activity and is useful for treating cellproliferative disease (Patent Document 20).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention.

Further, it is reported that the compound below has ALK, ROS, IGF-1R andInsR kinase inhibitory activity and is useful for treating cellproliferative disease (Patent Document 21).

(For the symbols in the formula, refer to the publication.)

However, there is no specific disclosure about the diamino heterocycliccarboxamide compounds according to the present invention.

CITATION LIST Patent Documents

-   Patent Document 1: European Patent Publication No. EP 1914240-   Patent Document 2: International Publication No. WO 2004/080980-   Patent Document 3: International Publication No. WO 00/75113-   Patent Document 4: International Publication No. WO 00/76980-   Patent Document 5: International Publication No. WO 2009/008371-   Patent Document 6: International Publication No. WO 2008/073687-   Patent Document 7: International Publication No. WO 2008/051547-   Patent Document 8: International Publication No. WO 2009/032703-   Patent Document 9: International Publication No. WO 2009/020990-   Patent Document 10: Japanese Patent Publication No. 2008-13499-   Patent Document 11: International Publication No. WO 2008/077885-   Patent Document 12: International Publication No. WO 2004/002964-   Patent Document 13: International Publication No. WO 2009/012421-   Patent Document 14: International Publication No. WO 2009/040399-   Patent Document 15: International Publication No. WO 2008/024974-   Patent Document 16: International Publication No. WO 2009/032694-   Patent Document 17: International Publication No. WO 2009/136995-   Patent Document 18: International Publication No. WO 2009/089042-   Patent Document 19: International Publication No. WO 2009/143389-   Patent Document 20: International Publication No. WO 2009/126514-   Patent Document 21: International Publication No. WO 2009/126515

Non-Patent Documents

-   Non-patent Document 1: International Journal of Cancer, vol. 100, p.    49, 2002-   Non-patent Document 2: Nature, vol. 448, no. 2, p. 561, 2007-   Non-patent Document 3: Laboratory Investigation, vol. 85, p. 1544,    2005-   Non-patent Document 4: Proceedings of the National Academy of    Science, vol. 104, no. 1, p. 270, 2007-   Non-patent Document 5: Cell, vol. 131, p. 1190, 2007-   Non-patent Document 6: Proceedings of the National Academy of    Science, vol. 104, no. 50, p. 19936, 2007

SUMMARY OF INVENTION Technical Problems

The present invention provides a compound which is useful as an activeingredient in pharmaceutical compositions, particularly pharmaceuticalcompositions for cancer therapy, and which can be used more safely as anactive ingredient in pharmaceutical compositions.

Solution to Problems

As a result of extensive and intensive studies on compounds useful asactive ingredients in pharmaceutical compositions for cancer therapy,the inventors of the present invention have found that the diaminoheterocyclic carboxamide compound of the present invention has excellentinhibitory activity against the kinase activity of EML4-ALK fusionproteins, and is useful as an active ingredient in pharmaceuticalcompositions for cancer therapy. This finding led to the completion ofthe present invention.

Namely, the present invention relates to a compound of formula (I) or asalt thereof, as well as a pharmaceutical composition comprising acompound of formula (I) or a salt thereof and an excipient.

(wherein the symbols are as defined below:

—X—: a group of formula (II) or (III)

A: —H, halogen, lower alkyl, cycloalkyl, or lower alkenyl;

R¹:

(1) phenyl substituted with one or more groups selected from Groups G₁and G₂ (provided that if —X— is a group of formula (II) and A is —H, orif —X— is a group of formula (III), R¹ is phenyl which is substitutedwith one or more groups selected from Group G₂ and may further besubstituted with one or more groups selected from Groups G₁ and G₂),(2) an aromatic heterocyclic ring which may be substituted with one ormore groups selected from Group G₃, or(3) a bicyclic fused ring which may be substituted with one or moreR^(ZA) (provided that naphthyl or benzodioxolyl which may be substitutedwith one or more R^(ZA) is excluded);

Group G₁: halogen, R⁰⁰, —O—R⁰⁰, —NHSO₂—R⁰⁰, —SO₂NH₂, —SO₂NH—R⁰⁰, amino,nitro, and cyano;

R⁰⁰: lower alkyl or lower alkenyl, each of which may be substituted withone or more halogens;

Group G₂: —SO₂—R⁰⁰, —SO₂N(R⁰⁰)₂, —CONH₂, —CON(R⁰⁰)₂, —NHCO—R⁰⁰,—N(R⁰⁰)CO—R⁰⁰, —NH—R⁰⁰, —CONH—(CH₂)_(n)—O—R⁰⁰, —O—(CH₂)_(n)—N(R⁰⁰)₂,—O—(CH₂)_(n)—O—(R⁰⁰), —O—(phenyl substituted with an aromaticheterocyclic ring), phenyl, aromatic heterocyclic ring, —W—Y—Z, and agroup of formula (IV)

n: an integer of 1 to 3.

L¹ and L²: L¹ and L², taken together with carbon atoms to which they arerespectively attached, form

(1) cycloalkyl which may be fused with phenyl, or

(2) a non-aromatic heterocyclic ring;

L³: a bond or methylene;

—W—: a bond, piperidine-1,4-diyl, or piperazine-1,4-diyl;

—Y—: a bond, —CO—, —SO₂—, —O—(CH₂)_(m)—, or —N(R⁰⁰)—(CH₂)_(m)—;

m: an integer of 0 to 3;

Z:

(1) R^(Z0), or

(2) a non-aromatic heterocyclic ring which may be substituted with oneor more groups selected from Group G_(A);

R^(Z0): cycloalkyl which may be substituted with one or more R⁰⁰;

Group G_(A): R⁰⁰ which may be substituted with a group selected from thegroup consisting of OH and R^(Z0), halogen, —SO₂—R⁰⁰, —CO—R⁰⁰, —COO—R⁰⁰,—N(R⁰⁰)₂, oxo, and —OH;

Group G₃: halogen, R⁰⁰, —O—R⁰⁰, phenyl, —O-phenyl, and —W—Z;

R^(ZA): R⁰⁰ or —(CH₂)_(n)—Z;

R²:

(1) cycloalkyl which may be substituted with one or more groups selectedfrom Group G₄ (it is to be noted that the cycloalkyl may be fused withphenyl or pyrazole, each of which may be substituted with one or more—O-lower alkyl),

(2) a non-aromatic heterocyclic ring which may be substituted with oneor more groups selected from Group G₄,

(3) phenyl which may be substituted with one or more groups selectedfrom Group G₄ excluding oxo,

(4) pyridyl which may be substituted with one or more groups selectedfrom Group G₄ excluding oxo, or

(5) lower alkyl which may be substituted with one or more groupsselected from Group G₅ (provided that 2-(dimethylamino)ethyl,2-(dimethylamino)propyl, and 2-(dimethylamino)butyl are excluded);

Group G₄: lower alkyl which may be substituted with a group selectedfrom Group G_(B), amino, —N(lower alkyl)₂, —NH-lower alkyl, —NHCO-loweralkyl, —NHCOO-lower alkyl, —CONH₂, —CONH—R^(ZB), —O-lower alkyl,—CO-lower alkyl, —COO-lower alkyl, —OH, —COOH, oxo, —SO₂-lower alkyl,R^(ZB), —CO—R^(ZB), cycloalkyl, and —W—Z;

Group G_(B): amino, —OH, cycloalkyl, and R^(ZB);

R^(ZB): phenyl which may be substituted with a group selected from thegroup consisting of halogen and —O-lower alkyl;

Group G₅:

(1) a group of Group G₄,

(2) cycloalkyl which may be substituted with one or more groups selectedfrom Group G₄,

(3) a non-aromatic heterocyclic ring which may be substituted with oneor more groups selected from Group G₄,

(4) phenyl which may be substituted with one or more groups selectedfrom Group G₄ excluding oxo, and

(5) pyridyl which may be substituted with one or more groups selectedfrom Group G₄ excluding oxo;

R³: —H or lower alkyl,

or R² and R³ taken together with nitrogen atoms to which they areattached may form cyclic amino which may be substituted with a groupselected from Group G₄.)

It is to be noted that in —SO₂N(R⁰⁰)₂, —CON(R⁰⁰)₂, —N(R⁰⁰)CO—R⁰⁰,—O—(CH₂)_(n)—N(R⁰⁰)₂, and —N(R⁰⁰)₂, two R⁰⁰ contained in each of thesegroups may be the same or different. Further, in —N(lower alkyl)₂, twolower alkyl may be the same or different.

Unless otherwise specified, when symbols used in one chemical formulaare also used in another chemical formula, the same symbols have thesame meanings.

The present invention also relates to an inhibitor against the kinaseactivity of EML4-ALK fusion protein, which comprises a compound offormula (I) or a salt thereof.

Moreover, the present invention also relates to a pharmaceuticalcomposition for cancer therapy, which comprises a compound of formula(I) or a salt thereof. It is to be noted that the pharmaceuticalcomposition includes a therapeutic agent for cancer, which comprises acompound of formula (I) or a salt thereof.

Moreover, the present invention also relates to the use of a compound offormula (I) or a salt thereof for the manufacture of a pharmaceuticalcomposition for cancer therapy, the use of a compound of formula (I) ora salt thereof for cancer therapy, as well as a method for cancertherapy, which comprises administering an effective amount of a compoundof formula (I) or a salt thereof to a patient.

Advantageous Effect of Invention

The compound of formula (I) or a salt thereof has inhibitory activityagainst the kinase activity of EML4-ALK fusion protein, as well asgrowth inhibitory activity against EML4-ALK fusion protein-dependentcells, and can be used as an active ingredient in pharmaceuticalcompositions for preventing and/or treating cancer, such as lung cancerin one embodiment, non-small cell lung cancer or small cell lung cancerin another embodiment, ALK fusion polynucleotide-positive cancer in yetanother embodiment, ALK fusion polynucleotide-positive lung cancer inyet another embodiment, ALK fusion polynucleotide-positive non-smallcell lung cancer in yet another embodiment, ALK fusion protein-positivecancer in yet another embodiment, ALK fusion protein-positive lungcancer in yet another embodiment, ALK fusion protein-positive non-smallcell lung cancer in yet another embodiment, EML4-ALK fusionpolynucleotide-positive cancer in yet another embodiment, EML4-ALKfusion polynucleotide-positive lung cancer in yet another embodiment,EML4-ALK fusion polynucleotide-positive non-small cell lung cancer inyet another embodiment, EML4-ALK fusion protein-positive cancer in yetanother embodiment, EML4-ALK fusion protein-positive lung cancer in yetanother embodiment, or EML4-ALK fusion protein-positive non-small celllung cancer in yet another embodiment.

DESCRIPTION OF EMBODIMENTS

The present invention will now be described in more detail below.

As used herein, the term “halogen” means F, Cl, Br or I.

The term “lower alkyl” refers to linear or branched alkyl containing 1to 6 carbon atoms (hereinafter abbreviated as “C₁₋₆”). Examples includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, n-hexyl, and the like. Another embodiment is C₁₋₄alkyl, and yet another embodiment is methyl, ethyl or isopropyl.

The term “lower alkenyl” refers to a monovalent group of a C₂₋₆ linearor branched hydrocarbon chain having at least one double bond. Examplesinclude vinyl, propenyl, isopropenyl, butenyl, pentenyl, 1-methylvinyl,1-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl, etc. Anotherembodiment is isopropenyl.

The term “cycloalkyl” refers to an optionally bridged C₃₋₁₀ saturatedcyclic hydrocarbon group, including cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl,bicyclo[3.1.1]heptyl, adamantyl, etc. Other examples include thosepartially unsaturated, such as cyclopentenyl, cyclohexenyl,cyclooctadienyl, bicyclo[3.1.1]heptenyl, etc.

The term “cyclic amino” refers to a monovalent group of a 3- to8-membered monocyclic non-aromatic cyclic amine which has at least onenitrogen atom and may further have the same or different one or moreheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, wherein at least one nitrogen atom has a binding hand. Specificexamples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,azepanyl, azocanyl, piperazinyl, homopiperazinyl, morpholinyl,oxazepanyl, thiomorpholinyl, thiazepanyl, and the like. Alternatively,another embodiment is a monovalent group of a 5- or 6-memberedmonocyclic non-aromatic cyclic amine. Yet another embodiment ispyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. It should benoted that such a ring may be bridged, as exemplified by2,5-diazabicyclo[2.2.1]heptyl, 9-azabicyclo[3.3.1]nonyl and the like, ormay have an unsaturated bond in part of the ring, as exemplified bydihydropyrrolyl, dihydropyridyl, tetrahydropyridyl, tetrahydropyrazyl,or the like.

The term “non-aromatic heterocyclic ring” refers to a monovalent groupof a 3- to 10-membered monocyclic non-aromatic heterocyclic ring whichhas 1 to 4 heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. Examples include aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, azepanyl, diazepanyl, azocanyl, piperazinyl,homopiperazinyl, morpholinyl, oxazepanyl, thiomorpholinyl, thiazepanyl,tetrahydropyranyl, tetrahydrofuryl, dioxanyl, dioxolanyl,tetrahydrothienyl, tetrahydrothiopyranyl, and the like. Anotherembodiment is a monovalent group of a 5- or 6-membered monocyclicnon-aromatic heterocyclic ring. It should be noted that such a ring maybe bridged, as exemplified by 2,5-diazabicyclo[2.2.1]heptyl,9-azabicyclo[3.3.1]nonyl or the like, or may have an unsaturated bond inpart of the ring, as exemplified by dihydropyrrolyl, dihydropyridyl,tetrahydropyridyl, tetrahydropyrazyl or the like.

The term “aromatic heterocyclic ring” refers to a monovalent group of a5- to 10-membered monocyclic aromatic heterocyclic ring which has 1 to 4heteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. Examples include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl,pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, thienyl, furyl,1,2,4-oxadiazolyl and the like. Another embodiment is pyridyl,imidazolyl, or pyrazolyl. Yet another embodiment is pyridyl.

The term “bicyclic fused ring” refers to (a) a monovalent group of a 9-to 11-membered bicyclic fused ring in which one of the two rings of the9- to 11-membered bicyclic fused ring is a 5- to 7-membered monocyclicheterocyclic ring having 1 to 3 heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur, and the other one of the tworings is a benzene ring (provided that benzodioxolyl is excluded), (b) amonovalent group of a 9- to 11-membered bicyclic fused ring in which oneof the two rings of the 9- to 11-membered bicyclic fused ring is C₅₋₇cycloalkyl, and the other one of the two rings is a benzene ring, or (c)azulenyl. Another embodiment is a monovalent group of a 9- to11-membered bicyclic fused ring in which one of the two rings of the 9-to 11-membered bicyclic fused ring is a 5- to 7-membered monocyclicheterocyclic ring having 1 to 3 heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur, and the other one of the tworings is a benzene ring (provided that benzodioxolyl is excluded), andexamples include quinolyl, benzothiazolyl, benzoimidazolyl, indolyl,indazolyl, benzothienyl, benzofuryl, tetrahydroisoquinolyl,2,3-dihydro-1,4-benzodioxynyl, 1,2,3-benzothiadiazolyl,2,1,3-benzothiadiazolyl, 3,4-dihydro-1,4-benzoxadinyl, etc. Yet anotherembodiment is azulenyl. It is to be noted that when one of the rings isa monocyclic heterocyclic ring having a saturated carbon atom, theserings may be substituted with oxo, as exemplified by3-oxo-3,4-dihydro-1,4-benzoxadinyl and1-oxo-1,2,3,4-tetrahydroisoquinolyl.

The term “ALK fusion polynucleotide” refers to a fusion polynucleotidein which the ALK gene is fused with another gene and thereby expressesan oncogenic fusion tyrosine kinase. Examples include EML4-ALK fusionpolynucleotide, TFG-ALK fusion polynucleotide, KIF5-ALK fusionpolynucleotide, NPM-ALK fusion polynucleotide, CLTCL-ALK fusionpolynucleotide, TPM3-ALK fusion polynucleotide, TPM4-ALK fusionpolynucleotide, ATIC-ALK fusion polynucleotide, CARS-ALK fusionpolynucleotide, SEC31L1-ALK fusion polynucleotide, RanBP2-ALK fusionpolynucleotide and the like.

The term “ALK fusion protein” refers to a fusion tyrosine kinaseproduced by expression of ALK fusion polynucleotide.

The term “EML4-ALK fusion polynucleotide” refers to a fusionpolynucleotide in which the ALK gene is fused with the EML4 gene andthereby expresses an oncogenic ALK fusion protein, including variantsthereof, such as EML4-ALK fusion polynucleotide v1 (polynucleotide ofSEQ ID NO: 1 of Patent Document 1), EML4-ALK fusion polynucleotide v2(polynucleotide of SEQ ID NO: 6 of Patent Document 1) and EML4-ALKfusion polynucleotide v3 (polynucleotide of SEQ ID NO: 129 of PatentDocument 1), as well as various variants (Annals of surgical oncology,vol. 17, p. 889, 2010, Molecular Cancer Research, vol. 7, p. 1466, 2009,Clinical Cancer Research, vo. 15, p. 3143, 2009, Cancer, vol. 115, p.1723, 2009, Clinical Cancer Research, vol. 14, p. 6618, 2008, ClinicalCancer Research, vol. 14, p. 4275, 2008, etc.).

The term “EML4-ALK fusion protein” refers to a fusion tyrosine kinasecreated by expression of EML4-ALK fusion polynucleotide.

A compound of formula (I) or a salt thereof wherein —X— in formula (I)represents a group of formula (II) means a compound of formula (V) or asalt thereof.

A compound of formula (I) or a salt thereof wherein —X— in formula (I)represents a group of formula (III) means a compound of formula (VI) ora salt thereof.

The phrase “may be substituted” is intended to mean “unsubstituted” or“having 1 to 5 substituents.” When substituted with a plurality ofgroups, these groups may be the same or different from each other.

The phrase “is (are) substituted” or “substituted” is intended to mean“having 1 to 5 substituents.” When substituted with a plurality ofgroups, these groups may be the same or different from each other.

The phrase “lower alkyl which may be substituted with one or morehalogens” refers to, for example, lower alkyl which may be substitutedwith the same or different 1 to 7 halogens. Another embodiment is loweralkyl which may be substituted with 1 to 5 halogens. Yet anotherembodiment is lower alkyl which may be substituted with 1 to 3 halogens.

The phrase “lower alkenyl which may be substituted with one or morehalogens” refers to, for example, lower alkenyl which may be substitutedwith 1 to 3 halogens.

Some embodiments of the compounds of formula (I) or a salt thereof aregiven below.

(1) Compounds of formula (I) or a salt thereof, wherein

(1-1) —X— is a group of formula (II), and A is halogen or lower alkyl,

(1-2) —X— is a group of formula (II), and A is a halogen,

(1-3) —X— is a group of formula (II), and A is lower alkyl,

(1-4) —X— is a group of formula (II), and A is chloro, ethyl orisopropyl,

(1-5) —X— is a group of formula (II), and A is chloro,

(1-6) —X— is a group of formula (II), and A is ethyl or isopropyl,

(1-7) —X— is a group of formula (II), and A is ethyl, or

(1-8) —X— is a group of formula (II), and A is isopropyl.

(2) Compounds of formula (I) or a salt thereof, wherein

(2-1) R¹ is phenyl which is substituted with —W—Y—Z and may further besubstituted with a group selected from the group consisting of halogen,R⁰⁰, —O—R⁰⁰, —NHSO₂—R⁰⁰, —SO₂NH—R⁰⁰, cyano, —SO₂—R⁰⁰, —SO₂N(R⁰⁰)₂,—CONH—R⁰⁰, —CON(R⁰⁰)₂, —NHCO—R⁰⁰, —N(R⁰⁰)CO—R⁰⁰, —O—(CH₂)_(n)—O—R⁰⁰, andcycloalkyl, R⁰⁰ is lower alkyl which may be substituted with one or morehalogens, —Y— is a bond, and Z is a non-aromatic heterocyclic ring whichmay be substituted with one or more groups selected from Group G_(A),

(2-2) R¹ is phenyl in which the carbon at the 4-position is substitutedwith —W—Y—Z and the carbon at the 3-position may be substituted with agroup selected from the group consisting of halogen, R⁰⁰, and —O—R⁰⁰,R⁰⁰ is lower alkyl which may be substituted with one or more halogens,—Y— is a bond, and Z is a non-aromatic heterocyclic ring which may besubstituted with one or more R⁰⁰,

(2-3) R¹ is phenyl in which the carbon at the 4-position is substitutedwith a group selected from the group consisting of4-(4-methylpiperazin-1-yl)piperidin-1-yl,4-(1-methylpiperidin-4-yl)piperazin-1-yl, 4-methylpiperazin-1-yl and4-isopropylpiperazin-1-yl and the carbon at the 3-position may besubstituted with a group selected from the group consisting of fluoro,methyl, trifluoromethyl and methoxy,

(2-4) R¹ is phenyl in which the carbon at the 4-position is substitutedwith 4-(4-methylpiperazin-1-yl)piperidin-1-yl and the carbon at the3-position may be substituted with a group selected from the groupconsisting of methyl, trifluoromethyl and methoxy,

(2-5) R¹ is phenyl in which the carbon at the 4-position is substitutedwith 4-methylpiperazin-1-yl and the carbon at the 3-position may besubstituted with a group selected from the group consisting of fluoroand methoxy,

(2-6) R¹ is 4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(2-7) R¹ is 3-methyl-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(2-8) R¹ is4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}-3-(trifluoromethyl)phenyl,

(2-9) R¹ is3-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(2-10) R¹ is 4-(4-methylpiperazin-1-yl)phenyl,

(2-11) R¹ is 3-fluoro-4-(4-methylpiperazin-1-yl)phenyl,

(2-12) R¹ is 3-methoxy-4-(4-methylpiperazin-1-yl)phenyl,

(2-13) R¹ is3-methyl-4-{4-(1-methylpiperidin-4-yl)piperazin-1-yl}phenyl, or

(2-14) R¹ is 4-(4-isopropylpiperazin-1-yl)-3-methylphenyl.

(3) Compounds of formula (I) or a salt thereof, wherein

(3-1) R² is

-   -   (i) cycloalkyl which may be substituted with one or more groups        selected from the group consisting of —N(lower alkyl)₂, lower        alkyl, —COO-lower alkyl, —OH, —COOH, —CONH—R^(ZB), and        morpholinyl, or    -   (ii) a non-aromatic heterocyclic ring which may be substituted        with one or more groups selected from the group consisting of        lower alkyl, —CO-lower alkyl, oxo, —CO—R^(ZB), and benzyl,

(3-2) R² is cycloalkyl which may be substituted with one or more groupsselected from the group consisting of —N(lower alkyl)₂, lower alkyl,—COO-lower alkyl, —OH, —COOH, —CONH—R^(ZB), and morpholinyl,

(3-3) R² is a non-aromatic heterocyclic ring which may be substitutedwith one or more groups selected from the group consisting of loweralkyl, —CO-lower alkyl, oxo, —CO—R^(ZB), and benzyl,

(3-4) R² is

-   -   (i) cyclohexyl which may be substituted with one or more groups        selected from the group consisting of —N(lower alkyl)₂, lower        alkyl, —COO-lower alkyl, —OH, —COOH, —CONH—R^(ZB), and        morpholinyl,    -   (ii) piperidinyl which may be substituted with one or more        groups selected from the group consisting of lower alkyl,        —CO-lower alkyl, oxo, —CO—R^(ZB), and benzyl, or    -   (iii) tetrahydropyranyl,

(3-5) R² is cyclohexyl which may be substituted with one or more groupsselected from the group consisting of —N(lower alkyl)₂, lower alkyl,—COO-lower alkyl, —OH, —COOH, —CONH—R^(ZB), and morpholinyl,

(3-6) R² is piperidinyl which may be substituted with one or more groupsselected from the group consisting of lower alkyl, —CO-lower alkyl, oxo,—CO—R^(ZB), and benzyl,

(3-7) R² is tetrahydropyranyl,

(3-8) R² is 4-hydroxycyclohexyl, 4-hydroxy-4-methylcyclohexyl, ortetrahydropyran-4-yl,

(3-9) R² is 4-hydroxycyclohexyl,

(3-10) R² is 4-hydroxy-4-methylcyclohexyl, or

(3-11) R² is tetrahydropyran-4-yl.

(4) Compounds of formula (I) or a salt thereof, wherein R³ is —H.

(5) Compounds, in which any combination of two or more of (1) to (4)shown above is applied. Examples of embodiments of the combinationinclude:

(5-1) Compounds or a salt thereof, in which (1) and (4) shown above areapplied,

(5-2) Compounds or a salt thereof, in which (1), (2), and (4) shownabove are applied,

(5-3) Compounds or a salt thereof, in which (1), (2), (3), and (4) shownabove are applied,

(5-4) Compounds or a salt thereof, in which (1-1), (2-1), (3-1), and (4)shown above are applied,

(5-5) Compounds or a salt thereof, in which (1-4), (2-1), (3-1), and (4)shown above are applied,

(5-6) Compounds or a salt thereof, in which (1-4), (2-2), (3-1), and (4)shown above are applied,

(5-7) Compounds or a salt thereof, in which (1-4), (2-3), (3-1), and (4)shown above are applied,

(5-8) Compounds or a salt thereof, in which (1-4), (2-3), (3-8), and (4)shown above are applied, and

(5-9) Compounds or a salt thereof, in which any consistent combinationof two or more selected from the group consisting of (1-5), (1-7),(1-8), (2-6), (2-7), (2-8), (2-9), (2-10), (2-11), (2-12), (2-13),(2-14), (3-9), (3-10), (3-11) and (4) shown above is applied.

Other embodiments of the compound of formula (I) or a salt thereof aregiven below.

(6) Compounds of formula (I) or a salt thereof, wherein

(6-1) —X— is a group of formula (II), and A is lower alkyl,

(6-2) —X— is a group of formula (II), and A is ethyl or isopropyl,

(6-3) —X— is a group of formula (II), and A is ethyl, or

(6-4) —X— is a group of formula (II), and A is isopropyl.

(7) Compounds of formula (I) or a salt thereof, wherein

(7-1) R¹ is phenyl in which the carbon at the 4-position is substitutedwith —W—Y—Z and, as another substituent, the carbon at the 2- or3-position may be substituted with R⁰⁰ or —O—R⁰⁰, and —Y— is a bond,

(7-2) R¹ is phenyl in which the carbon at the 4-position is substitutedwith —W—Y—Z and, as another substituent, the carbon at the carbon at the3-position may be substituted with R⁰⁰ or —O—R⁰⁰, —W— ispiperidine-1,4-diyl (attached via the nitrogen atom to phenyl to which—W— is attached) or a bond, —Y— is a bond, and —Z is piperazin-1-yl inwhich the nitrogen atom at the 4-position may be substituted with loweralkyl,

(7-3) R¹ is phenyl in which the carbon at the 4-position is substitutedwith 4-(4-methylpiperazin-1-yl)piperidin-1-yl and, as anothersubstituent, the carbon at the 3-position may be substituted withmethyl, trifluoromethyl, methoxy, or ethoxy,

(7-4) R¹ is 3-methyl-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(7-5) R¹ is4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}-3-(trifluoromethyl)phenyl,

(7-6) R¹ is3-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(7-7) R¹ is 3-ethoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(7-8) R¹ is 4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(7-9) R¹ is phenyl in which the carbon at the 4-position is substitutedwith 4-methylpiperazin-1-yl or 4-isopropylpiperazin-1-yl and, as anothersubstituent, the carbon at the 3-position may be substituted withmethyl, trifluoromethyl, or methoxy,

(7-10) R¹ is 3-methyl-4-(4-methylpiperazin-1-yl)phenyl,

(7-11) R¹ is 4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl,

(7-12) R¹ is 3-methoxy-4-(4-methylpiperazin-1-yl)phenyl,

(7-13) R¹ is 4-(4-methylpiperazin-1-yl)phenyl,

(7-14) R¹ is 4-(4-isopropylpiperazin-1-yl)-3-methylphenyl,

(7-15) R¹ is phenyl in which the carbon at the 3-position is substitutedwith —SO₂—R⁰⁰,

(7-16) R¹ is 3-(methylsulfonyl)phenyl,

(7-17) R¹ is phenyl in which the carbon at the 3-position is substitutedwith —W—Y—Z and, as another substituent, the carbon at the 4-positionmay be substituted with —O—R⁰⁰, —W— is a bond, and —Y— is a bond,

(7-18) R¹ is phenyl in which the carbon at the 3-position is substitutedwith 4-methylpiperazin-1-yl and, as another substituent, the carbon atthe 4-position may be substituted with methoxy,

(7-19) R¹ is 4-methoxy-3-(4-methylpiperazin-1-yl)phenyl,

(7-20) R¹ is 3-(4-methylpiperazin-1-yl)phenyl,

(7-21) R¹ is2-methoxy-4-{4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl,

(7-22) R¹ is 1-methylindazol-6-yl,

(7-23) R¹ is 4-morpholin-4-ylphenyl,

(7-24) R¹ is 4-(1-methylpiperidin-4-yl)phenyl,

(7-25) R¹ is4-{4-(cyclopropylmethyl)piperazin-1-yl}-3-(trifluoromethyl)phenyl, or

(7-26) R¹ is4-{3-(dimethylamino)pyrrolidin-1-yl}-3-(trifluoromethyl)phenyl.

(8) Compounds of formula (I) or a salt thereof, wherein

(8-1) R² is cycloalkyl substituted with —OH and lower alkyl,

(8-2) R² is cyclohexyl substituted with —OH and lower alkyl,

(8-3) R² is cyclohexyl in which the carbon at the 4-position issubstituted with —OH and lower alkyl,

(8-4) R² is cyclohexyl in which the carbon at the 4-position issubstituted with —OH and methyl,

(8-5) R² is cycloalkyl substituted with —OH,

(8-6) R² is cyclohexyl substituted with —OH,

(8-7) R² is 4-hydroxycyclohexyl,

(8-8) R² is a non-aromatic heterocyclic ring which may be substitutedwith lower alkyl,

(8-9) R² is tetrahydropyranyl which may be substituted with lower alkyl,or piperidinyl which may be substituted with lower alkyl,

(8-10) R² is tetrahydropyran-4-yl,

(8-11) R² is piperidin-4-yl in which the nitrogen atom at the 1-positionmay be substituted with lower alkyl,

(8-12) R² is 1-methylpiperidin-4-yl, or

(8-13) R² is piperidin-4-yl.

(9) Compounds of formula (I) or a salt thereof, wherein R³ is —H.

(10) Compounds of (6-3) shown above or a salt thereof.

(11) Compounds of (7-4), (7-5), (7-6), (7-7), (7-8), (7-10), (7-13), or(7-14) shown above or a salt thereof.

(12) Compounds of (8-4), (8-7), (8-10), or (8-13) shown above or a saltthereof.

(13) Compounds, in which

(13-1) any combination of two or more of (6) to (9) shown above isapplied, or a salt thereof, or

(13-2) any combination of two or more of (9) to (12) shown above isapplied, or a salt thereof.

Examples of specific compounds falling within the present inventioninclude the following compounds.

-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazin-1-yl)-3-methylphenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,-   6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,-   6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,-   6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,-   6-ethyl-3-{[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,-   6-isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,-   6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,    or-   6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,    or a salt thereof.

Examples of specific compounds falling within the present inventioninclude those selected from Compound groups P and Q shown below.

Compound group P:

-   a group consisting of    6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazin-1-yl)-3-methylphenyl]amino}pyrazine-2-carboxamide,-   3-({3-ethoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,-   6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(piperidin-4-ylamino)pyrazine-2-carboxamide,-   6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,-   6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,    and-   6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl}phenyl]amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,    as well as salts of these compounds.    Compound group Q:-   a group consisting of    6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(1-methyl-1H-indazol-6-yl)amino]pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(4-morpholin-4-ylphenyl)amino]pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(1-methylpiperidin-4-yl)phenyl]amino}pyrazine-2-carboxamide,-   5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,-   3-({4-[4-(cyclopropylmethyl)piperazin-1-yl]-3-(trifluoromethyl)phenyl}amino)-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide,-   3-({4-[3-(dimethylamino)pyrrolidin-1-yl]-3-(trifluoromethyl)phenyl}amino)-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide,-   6-ethyl-5-[(cis-4-ethyl-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-ethyl-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(cis-4-hydroxy-4-isopropylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,-   6-ethyl-5-[(trans-4-hydroxy-4-isopropylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,    and-   6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-[(1-methylpiperidin-4-yl)amino]pyrazine-2-carboxamide,    as well as salts of these compounds.

The compounds of formula (I) may have tautomers and/or geometricalisomers (including cis-trans isomers of compounds having a saturatedring group such as a cycloalkyl group), depending on the type of theirsubstituents. Even when the compounds of formula (I) appear herein onlyin one isomer form, the present invention encompasses the other isomers,and also encompasses separated isomers or mixtures thereof.

Further, since some compounds of formula (I) have an asymmetric carbonatom or axial asymmetry, optical isomers based on this asymmetry mayalso exist. The present invention also encompasses separated opticalisomers of the compounds of formula (I) or mixtures thereof.

Furthermore, the present invention encompasses pharmaceuticallyacceptable prodrugs of the compounds represented by formula (I). Theterm “pharmaceutically acceptable prodrug” refers to a compound having agroup which can be converted into an amino group, a hydroxyl group, acarboxyl group or the like by solvolysis or under physiologicalconditions. Examples of a prodrug-forming group include those describedin Prog. Med., 5, 2157-2161 (1985) or those described in “Development ofPharmaceuticals” (Hirokawa Publishing, 1990) vol. 7, Molecular Design163-198.

Likewise, salts of the compounds of formula (I) are pharmaceuticallyacceptable salts of the compounds of formula (I). The compounds offormula (I) may form acid or base addition salts, depending on the typeof their substituents. Specific examples include acid addition saltswith inorganic acids (e.g., hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike) or with organic acids (e.g., formic acid, acetic acid, propionicacid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleicacid, lactic acid, malic acid, mandelic acid, tartaric acid,dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like),salts with inorganic bases (e.g., sodium, potassium, magnesium, calcium,aluminum, and the like) or with organic bases (e.g., methylamine,ethylamine, ethanolamine, lysine, ornithine, and the like), salts withvarious amino acids and amino acid derivatives (e.g., acetylleucine, andthe like), as well as ammonium salt, etc.

Moreover, the present invention also encompasses the compounds offormula (I) and salts thereof in the form of various hydrates, solvates,and crystalline polymorphic substances. The present invention alsoencompasses the compounds labeled with various radioactive ornon-radioactive isotopes.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof can be prepared by applying various known synthesis methods onthe basis of characteristics derived from their skeletal structure orthe type of their substituents. In some cases, depending on the type offunctional group, it is technically effective to replace such afunctional group with an appropriate protecting group (a group which canbe easily converted into the original functional group) at the startingmaterial stage or at the intermediate stage. Examples of such aprotecting group include those described in Greene and Wuts, “Greene'sProtective Groups in Organic Synthesis (fourth edition, 2007)” and soon, which may be selected and used as appropriate, depending on reactionconditions. In such a method, after introduction of the protecting groupand subsequent reaction, the protecting group may be removed ifnecessary to obtain a desired compound.

Likewise, a prodrug of the compound of formula (I) can be prepared byintroducing a specific group at the starting material stage or at theintermediate stage, as in the case of the above protecting group, or bysubjecting the obtained compound of formula (I) to further reaction. Thereaction may be accomplished by applying conventional esterification,amidation, dehydration or other techniques known to those skilled in theart.

Explanation will be given below of typical processes for preparing thecompounds of formula (I). Each process may also be accomplished byreference to the documents cited in this explanation. It should be notedthat the processes of the present invention are not limited to theexamples illustrated below.

(Preparation Process 1)

(In the formula, -L_(A) represents a leaving group, and examples includelower alkylsulfanyl.)

This process is intended to prepare the compound of the presentinvention (I-a) by reacting compound (1a) with compound (2).

In this reaction, compounds (1a) and (2) are used in equal amounts orone of them is used in an excessive amount. A mixture of these compoundsis stirred in a solvent inert to the reaction or in the absence of asolvent under cooling to reflux conditions, preferably at 0° C. to 200°C., generally for 0.1 hours to 5 days. The reaction may be performedusing a microwave reaction system, because it is advantageous for smoothreaction in some cases. A solvent used for this purpose is notparticularly limited, as long as it is inert to the reaction, andexamples include aromatic hydrocarbons (e.g., benzene, toluene, xylene),ethers (e.g., diethyl ether, tetrahydrofuran (THF), dioxane,dimethoxyethane), halogenated hydrocarbons (e.g., 1,2-dichloroethane,chloroform), alcohols (e.g., methanol, ethanol, 2-propanol),1-methyl-2-pyrrolidinone (NMP), N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), 1,3-dimethyl-2-imidazolidinone (DMI),dimethyl sulfoxide (DMSO), acetonitrile, and mixtures thereof. Thereaction may be performed in the presence of an organic base (e.g.,triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, or thelike) or an inorganic base (e.g., potassium carbonate, sodium carbonate,potassium hydroxide, or the like), because it is advantageous for smoothreaction in some cases.

When the reaction is performed in the presence of such a base as shownabove, depending on the properties or the like of starting compounds,the desired reaction is impossible or difficult to proceed, for example,due to decomposition or the like of the starting compounds. In thiscase, the reaction may be performed in the presence of a mineral acid(e.g., hydrochloric acid, hydrobromic acid, and the like), an organicacid (e.g., acetic acid, propionic acid, and the like) or a sulfonicacid (e.g., methanesulfonic acid, p-toluenesulfonic acid, and the like),because it is advantageous for smooth reaction in some cases. Further,when -L_(A) is lower alkylsulfanyl, the S atom may be oxidized withvarious oxidizing agents such as Oxone®, m-chloroperbenzoic acid (mCPBA)and peracetic acid to convert the lower alkylsulfanyl into loweralkylsulfinyl or lower alkylsulfonyl and then the lower alkylsulfinyl orlower alkylsulfonyl may be reacted with compound (2), because it isadvantageous for smooth reaction in some cases.

Documents

-   S. R. Sandler and W. Karo, “Organic Functional Group Preparations,”    second edition, vol. 1, Academic Press Inc., 1991-   The Chemical Society of Japan, “Fifth Series of Experimental    Chemistry,” vol. 14 (2005) (MARUZEN Co., Ltd., Japan)    (Preparation Process 2)

(In the formula, -L_(B) represents a leaving group, and examples includea halogen (e.g., F, Cl), a sulfonyloxy group (e.g., methanesulfonyloxy,p-toluenesulfonyloxy, trifluoromethanesulfonyloxy), lower alkylsulfanyl,and lower alkylsulfonyl.)

This process is intended to prepare the compound of the presentinvention (I-b) by reacting compound (1b) with compound (2).

In this reaction, the procedure of Preparation Process 1 may be applied.

(Starting Material Synthesis 1)

(In the formula, -L_(C) represents a leaving group, and examples includea halogen (e.g., F, Cl) and a sulfonyloxy group (e.g.,methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy);R^(A) represents acyl, benzyl, lower alkyl, or —H; and M represents analkali metal.)

This process is intended to prepare compound (1a) by reacting compound(5), which is obtained by reacting compound (3) with compound (4), withcompound (6) and thereafter subjecting to deprotection reaction toremove R^(A).

In the reaction which gives compound (5), the procedure of PreparationProcess 1 may be applied. In the reaction which gives compound (1a), theprocedure of Preparation Process 1 may be applied and the reaction maybe performed using compound (6) or a reagent which produces compound (6)in the system, and thereafter deprotection reaction may be conductedunder reaction conditions which are selected as appropriate from, forexample, reaction conditions described in Greene and Wuts, “Greene'sProtective Groups in Organic Synthesis (fourth edition, 2007).” Examplesof compound (6) include sodium acetate and sodium methoxide. It is to benoted that compound (1a) can also be prepared by performing the reactionusing a hydrogen peroxide solution in place of compound (6) andthereafter performing acid treatment with hydrochloric acid or the like.

(Starting Material Synthesis 2)

This process is intended to prepare compound (1b) by reacting compound(7) with compound (4).

In this reaction, the procedure of Preparation Process 1 may be applied.

The compound of formula (I) is isolated and purified as a free compoundor as a pharmaceutically acceptable salt, hydrate, solvate orcrystalline polymorphic substance thereof. A pharmaceutically acceptablesalt of the compound of formula (I) may also be prepared by beingsubjected to conventional salt-forming reaction.

Isolation and purification may be accomplished by applying conventionalchemical operations such as extraction, fractional crystallization,various types of fractionation chromatography, etc.

Various isomers can be prepared by selecting appropriate startingcompounds or can be separated on the basis of differences in thephysical and chemical properties of isomers. For example, opticalisomers can be derived into optically pure isomers by conventionaloptical resolution techniques (e.g., fractional crystallizationresulting in a diastereomer salt with an optically active base or acid,chromatography on a chiral column or the like, and the like). They canalso be prepared from appropriate optically active starting compounds.

The compounds of formula (I) were confirmed for their pharmacologicalactivity in the following tests. Unless otherwise specified, the testexamples shown below may be accomplished by a method described in EP1914240 or any publicly-known method and, when using commerciallyavailable reagents, kits, or the like, may be accomplished in accordancewith the instructions attached to these commercially available products.It is to be noted that the term “EML4-ALK fusion protein v1” refers to apolypeptide of the amino acid sequence represented by SEQ ID NO: 2 ofPatent Document 1, and the term “EML4-ALK fusion protein v3” refers to apolypeptide of the amino acid sequence represented by SEQ ID NO: 130 ofPatent Document 1.

Test Example 1 Evaluation of Inhibitory Activity Against the KinaseActivity of EML4-ALK Fusion Protein

A recombinant retrovirus was created from expression plasmidFLAG-EML4-ALKv1/pMX-iresCD8 in which cDNA for EML4-ALK fusion protein v1was integrated, and injected into mouse lymphoid cell line BA/F3 cells.Using a magnetic bead reagent for cell separation and a purificationcolumn (anti-CD8 monoclonal antibody immobilized on magnetic beads and aMiniMACS purification column; both are products of Miltenyi BiotecInc.), cell surface CD8-expressing cells were purified to establishEML4-ALK fusion protein v1-expressing BA/F3 cells. From the cells,EML4-ALK fusion protein v1 was purified and subjected to kinase activityevaluation. EML4-ALK fusion protein v1 was investigated for itsphosphorylation activity toward a peptide substrate by using a kinaseactivity detection kit (HTRF KinEASE-TK; Cisbio Inc.). Test compoundswere each added to a reaction solution containing the enzyme protein togive 8 final concentrations from 1000 nM to 0.3 nM, followed by additionof ATP and reaction for 1 hour. The ATP concentration used was 100 μM.Another reaction solution was prepared to contain the enzyme protein butno test compound (in which the solvent DMSO alone was added at 0.4% inplace of the test compound), followed by reaction in the same mannerwith or without ATP addition. In the absence of the test compound, thephosphorylation count without ATP addition and with ATP addition wasassumed to be 100% inhibition and 0% inhibition, respectively. Theconcentration causing 50% inhibition (IC₅₀) was calculated for each testcompound by the logistic regression method.

As a result, some compounds of the present invention were found to haveinhibitory activity against the kinase activity of EML4-ALK fusionprotein v1. Table 1 shows the IC₅₀ values obtained for some compounds ofthe present invention. Ex denotes Example No. In the table below,Compound X denotes a racemic form of the compound of Example 174 shownin International Publication No. WO 2009/136995(rac-2-{[(1R,2S)-2-aminocyclohexyl]amino}-4-{[4′-(morpholin-4-yl)biphenyl-4-yl]amino}pyrimidine-5-carboxamide),and Compound Y denotes the compound of Examples 26-22 shown inInternational Publication No. WO 00/76980(5-{[2-(dimethylamino)ethyl]amino}-6-ethyl-3-[(3-methylphenyl)amino]pyrazine-2-carboxamide).

TABLE 1 Ex IC₅₀(nM)  86 17 110 0.99 284 8.9 325 5.3 328 76 340 0.37 3412.8 343 2.1 347 1.7 354 0.77 355 0.33 357 17 370 0.65 377 0.24 378 0.26383 0.23 387 0.26 388 0.17 391 0.22 392 0.21 399 0.94 406 0.34 426 0.49459 0.26 466 0.93 490 3.1 491 2.8 493 2.6 494 4.1 512 1.5 534 1.0 5382.3 544 1.9 545 11 546 7.8 547 1.5 549 2.1 550 11 553 1.4 554 4.5 5582.2 Compound X 220 Compound Y >1000

Test Example 2 Evaluation of Growth Inhibitory Activity Against EML4-ALKFusion Protein-Dependent Cells

EML4-ALK fusion protein v1-expressing BA/F3 cells can grow in theabsence of IL-3. In other words, they are cells that EML4-ALK fusionprotein v1-dependently grow.

In a 96-well plate (Iwaki), BA/F3 cells expressing EML4-ALK fusionprotein v1 were seeded at 500 cells per well in RPMI1640 medium(Invitrogen) containing 10% fetal bovine serum, followed by addition ofa test compound (final concentration: 10 μM to 0.1 nM). As a negativecontrol, DMSO used as a solvent of the test compound was added. Then,the cells were cultured under 5% CO₂ at 37° C. for 2 days. A cellcounting reagent (AlmarBlue; Biosource) was added, and the cells werecultured for 150 minutes, followed by measurement of fluorescenceintensity with a luminometer (Safire; Tecan) in accordance withinstructions attached to the reagent. Assuming that the value measuredfor the medium alone and the value measured for the negative controlwere 100% inhibition and 0% inhibition, respectively, the inhibitionrate was calculated for each compound to thereby determine theconcentration causing 50% inhibition (IC₅₀ value) by the logisticregression method.

As a result, some compounds of the present invention showed growthinhibitory activity against BA/F3 cells expressing EML4-ALK fusionprotein v1. Table 2 shows the IC₅₀ values obtained for some compounds ofthe present invention. Ex denotes Example No. In the table below,Compound X and Compound Y respectively denote the compounds described inTest Example 1.

TABLE 2 Ex IC₅₀(nM)  86 68 110 64 284 85 325 20 328 76 340 9.5 341 11343 11 347 17 354 8.6 355 9.2 357 60 370 4.9 377 6.9 378 6.1 383 5.9 38710 388 4.1 391 6.5 392 6.3 399 11 406 9.8 426 11 459 8.1 466 9.3 490 18491 16 493 19 494 42 512 19 534 24 538 7.7 544 27 545 25 546 23 547 5.7549 14 550 39 553 4.7 554 14 558 16 Compound X 821 Compound Y >1000

From the results of Test Examples 1 and 2 shown above, it was confirmedthat the compounds of the present invention had inhibitory activityagainst the kinase activity of EML4-ALK fusion protein v1 and growthinhibitory activity against EML4-ALK fusion protein v1-expressing BA/F3cells. On the other hand, Compounds X and Y described in Test Example 1were confirmed to have extremely weak inhibitory activity against thekinase activity of EML4-ALK fusion protein v1 and growth inhibitoryactivity against EML4-ALK fusion protein v1-expressing BA/F3 cells,compared with the compounds of the present invention.

Test Example 3 Antitumor Test (In Vivo) on EML4-ALK FusionProtein-Dependent Cells

Expression plasmid EML4-ALKv1/pMXS in which cDNA for EML4-ALK fusionprotein v1 was integrated was trasfected into 3T3 fibroblast cells bythe phosphate calcium method to thereby establish EML4-ALK fusionprotein v1 expressing 3T3 cells. 3×10⁶ cells of EML4-ALK fusion proteinv1 expressing 3T3 cells suspended in PBS were inoculated subcutaneouslyby injection to the back of 5 weeks old male Balb/c nude mice (CharlesRiver Japan, Inc.). After 7 days of the inoculation, the administrationof test compound was initiated. The test was conducted in the solventgroup and the compound group, 4 animals per group. The test compound wassuspended in a solvent composed of 0.5% methylcellulose and administeredorally at a dose of 10 mg/kg. Administrations were performed once a dayfor 5 days, and body weight and tumor size were measured every otherday. Tumor volume was calculated using the following formula.[Tumor volume(mm³)]=[Tumor major axis(mm)]×[tumor minor axis(mm)]²×0.5

Assuming that the tumor volume of the solvent group on the day ofstarting and the day of finishing administration of the test compoundwas 100% inhibition and 0% inhibition, respectively, the inhibition rateof the test compound was calculated. When regression of tumor volume isinduced from the day of starting administration, the tumor volume on theday of starting administration and the state in which the tumordisappeared were assumed to be 0% regression and 100% regression,respectively, and the rate of regression of the test compound wascalculated.

As a result, it was confirmed that among the compounds of the presentinvention, there were compounds that inhibited growth of tumor ofEML4-ALK fusion protein v1 expressing 3T3 cells and compounds thatinduced regression of tumor of EML4-ALK fusion protein v1 expressing 3T3cells. Table 3 shows the inhibition rate of some compounds of thepresent invention. It is to be noted that in the table below, thenumerical values specified with “(regression)” each indicate a rate ofregression. Ex denotes Example No.

TABLE 3 Ex (%) 370 81 378 92 392 28 (regression) 426 81 466 54(regression) 546 79 549 67 (regression) 553 63 558 37 (regression)

Thus, when orally administered, the compounds of the present inventioninhibited tumor growth in mice inoculated with EML4-ALK fusion proteinv1 expressing 3T3 cells or induced regression of tumor, therebyconfirming that the compounds of the present invention had oralactivity.

Test Example 4 Antitumor Test (In Vivo) on EML4-ALK FusionProtein-Dependent Cells

The antitumor effects on EML4-ALK fusion protein-dependent cells canalso be confirmed by use of human non-small cell lung cancers cell lineNCI-H2228 cells (cells derived from EML4-ALK fusionpolynucleotide-positive lung cancer patients (EML4-ALK fusion proteinv3-dependent cells)) in place of the EML4-ALK fusion protein v1expressing 3T3 cells of Test Example 3, as shown below.

3×10⁶ cells of NCI-H2228 cells suspended in 50% Matrigel (Invitrogen)were inoculated subcutaneously by injection to the back of 5 weeks oldmale NOD/SCID mice (Charles River Japan, Inc.). After 3 weeks of theinoculation, the administration of test compounds was initiated. Thetest was conducted in the solvent group and test compound groups, 6animals per group. The test compounds were each dissolved in a solventcomposed of 10% 1-methyl-2-pyrrolidinone (SIGMA-ALDRICH Inc.)/90%polyethylene glycol 300 (Fluka Inc.) and administered orally at a doseof 1 mg/kg. Administrations were performed once a day for 14 days, andbody weight and tumor size were measured every other day. Tumor volumewas calculated using the following formula.[Tumor volume(mm³)]=[Tumor major axis(mm)]×[tumor minor axis(mm)]²×0.5

Assuming that the tumor volume of the solvent group on the day ofstarting and the day of finishing administration was 100% inhibition and0% inhibition, respectively, the inhibition rate was calculated for eachcompound.

As a result, it was confirmed that among the compounds of the presentinvention, there were compounds that inhibited growth of tumor ofNCI-H2228 cells. For example, the compound of Example 549 inhibitedgrowth of tumor of NCI-H2228 cells by 69%.

Thus, when orally administered, the compounds of the present inventioninhibited tumor growth in mice inoculated with human non-small cell lungcancer cell line NCI-H2228 cells, thereby confirming that the compoundsof the present invention had oral activity.

On the other hand, when Compounds X and Y described in Test Example 1were administered, no significant growth inhibition against NCI-H2228cells (tumor) was shown, compared with the solvent group. Thesignificance test was conducted by Student's t-test.

In view of the foregoing, in Test Examples 1 and 2, the compounds of thepresent invention were confirmed to have inhibitory activity against thekinase activity of EML4-ALK fusion protein, as well as growth inhibitoryactivity against EML4-ALK fusion protein-dependent cells. Further, inTest Examples 3 and 4, the compounds of the present invention were alsoconfirmed to have an antitumor effect on EML4-ALK fusionprotein-dependent cells (tumor) based on the above actions. Theseindicate that the compounds of the present invention are useful asactive ingredients in pharmaceutical compositions for preventing and/ortreating cancer, such as lung cancer in one embodiment, non-small celllung cancer or small cell lung cancer in another embodiment, ALK fusionpolynucleotide-positive cancer in yet another embodiment, ALK fusionpolynucleotide-positive lung cancer in yet another embodiment, ALKfusion polynucleotide-positive non-small cell lung cancer in yet anotherembodiment, ALK fusion protein-positive cancer in yet anotherembodiment, ALK fusion protein-positive lung cancer in yet anotherembodiment, ALK fusion protein-positive non-small cell lung cancer inyet another embodiment, EML4-ALK fusion polynucleotide-positive cancerin yet another embodiment, EML4-ALK fusion polynucleotide-positive lungcancer in yet another embodiment, EML4-ALK fusionpolynucleotide-positive non-small cell lung cancer in yet anotherembodiment, EML4-ALK fusion protein-positive cancer in yet anotherembodiment, EML4-ALK fusion protein-positive lung cancer in yet anotherembodiment, or EML4-ALK fusion protein-positive non-small cell lungcancer in yet another embodiment.

So far, as to the ALK gene, the presence of various types of activepoint mutation and overexpression associated with gene amplificationhave been confirmed in cells derived from neuroblastoma patients(Nature, vol. 455, p. 971, 2008; Cancer Research, vol. 68, p. 3389,2008). Further, it is known that a compound having inhibitory activityagainst the kinase activity of ALK protein shows an antitumor effect oncells derived from mutant ALK polynucleotide-positive cancer patientsand cells derived from cancer patients with overexpression of ALKpolynucleotide (Cancer Research, vol. 68, p. 3389, 2008). These indicatethat the compounds of the present invention are useful as activeingredients in pharmaceutical compositions for preventing and/ortreating neuroblastoma, such as mutant ALK polynucleotide-positivecancer in one embodiment, cancer with overexpression of ALKpolynucleotide in another embodiment, mutant ALK polynucleotide-positiveneuroblastoma in yet another embodiment, or neuroblastoma withoverexpression of ALK polynucleotide in yet another embodiment.

The compounds of formula (I) were also confirmed for theirpharmacological activity in the following tests. Unless otherwisespecified, the test examples shown below may be accomplished in a knownmanner and, when using commercially available reagents and/or kits, maybe accomplished in accordance with the instructions attached to thesecommercially available products.

Test Example 5 Evaluation of Inhibitory Activity Against the KinaseActivity of RET Protein

A partial protein of only a kinase domain of RET protein was purchasedfrom Carna Biosciences Inc., Japan. The phosphorylation activity towarda peptide substrate was investigated using an EZ reader (Caliper). Testcompounds were each mixed with a protein solution to give 8 finalconcentrations from 100 nM to 0.03 nM, followed by addition of a mixedliquid of ATP and substrate peptide (Caliper) and reaction for 30minutes. The ATP concentration used was 100 μM. A reaction liquid whichcontained protein but no test compound (in which the solvent DMSO alonewas added at 0.8% in place of the test compound) was prepared, followedby reaction in the same manner with or without ATP addition. In theabsence of the test compound, the phosphorylation peptide peak withoutATP addition and with ATP addition was assumed to be 100% inhibition and0% inhibition, respectively. The test compound concentration causing 50%inhibition (IC₅₀ value) was calculated by the logistic regressionmethod.

As a result, some compounds of the present invention showed inhibitoryactivity against the kinase activity of RET protein. Table 4 shows theIC₅₀ values obtained for some compounds of the present invention. Exdenotes Example No.

TABLE 4 Ex IC₅₀(nM) 565 1.1 566  0.95 567 1.7 568 1.5 569 1.0 570 2.3571 1.1 572 1.3 573 1.0 574 1.0 575 1.3 576 1.3 577 3.4 578 1.5 579 1.1580 3.6 581 2.9 582 1.1

RET (Rearranged during transfection) is a receptor tyrosine kinase andis a protein having a transmembrane region in the middle part, flankedby a tyrosine kinase region on the carboxyl-terminal side and anextracellular region on the amino-terminal side.

From the results of Test Example 5, it was confirmed that the compoundsof the present invention had inhibitory activity against the kinaseactivity of RET protein. So far, as to the RET gene, active pointmutation has been confirmed in cells or cancer tissue specimens derivedfrom non-small cell lung cancers, small cell lung cancer, thyroidcancer, adrenal pheochromocytoma, colon cancer, and pancreatic cancer,and fusion with H4, H4L, PRKAR1A, NCOA4, GOLGA5, HTIF1, TIF1G, TKTN1,RFG9, ELKS, PCM1, RFP, and HOOK3 genes has been confirmed in cells orcancer tissue specimens derived from thyroid cancer, ovarian cancer, andmesothelioma (point mutation in non-small cell lung cancer: NatureGenetics, 2007, 39, 347-351; point mutation in small cell lung cancer:Japanese Journal of Cancer Research, 1995, 86, 1127-1130; fusion andpoint mutation in thyroid cancer: Endocrine Reviews, 2006, 27, 535-560;point mutation in adrenal tumor: Journal of Clinical Endocrinology andMetabolism, 1996, 81, 2041-2046; point mutation in colon cancer:Science, 2006, 314, 268-274; point mutation in pancreatic cancer: CancerResearch, 2005, 65, 11536-11544; fusion in ovarian cancer: InternationalJournal of Surgical Pathology, 2009, 17, 107-110; fusion inmesothelioma: Cancer letters, 2008, 265, 55-66). Further, it is knownthat a compound having inhibitory activity against the kinase activityof RET protein shows an antitumor effect on cells derived from mutantRET polynucleotide-positive cancer patients and cells derived fromfusion RET polynucleotide-positive cancer patients (Endocrine Reviews,2006, 27, 535-560). These indicate that the compounds of the presentinvention are useful as active ingredients in pharmaceuticalcompositions for preventing and/or treating thyroid cancer, such asadrenal pheochromocytoma in one embodiment, colon cancer in anotherembodiment, pancreatic cancer in yet another embodiment, ovarian cancerin yet another embodiment, mesothelioma in yet another embodiment,mutant RET polynucleotide-positive cancer in yet another embodiment,mutant RET polynucleotide-positive lung cancer in yet anotherembodiment, mutant RET polynucleotide-positive non-small cell lungcancer in yet another embodiment, mutant RET polynucleotide-positivesmall cell lung cancer in yet another embodiment, mutant RETpolynucleotide-positive thyroid cancer in yet another embodiment, mutantRET polynucleotide-positive adrenal pheochromocytoma in yet anotherembodiment, mutant RET polynucleotide-positive colon cancer in yetanother embodiment, mutant RET polynucleotide-positive pancreatic cancerin yet another embodiment, RET fusion polynucleotide-positive cancer inyet another embodiment, RET fusion polynucleotide-positive thyroidcancer in yet another embodiment, RET fusion polynucleotide-positiveovarian cancer in yet another embodiment, or RET fusionpolynucleotide-positive mesothelioma in yet another embodiment.

Test Example 6 Evaluation of Inhibitory Activity Against the KinaseActivity of ROS Protein

A partial protein of only a kinase domain of ROS protein was purchasedfrom Carna Biosciences Inc., Japan, and tests were conducted as in TestExample 5, except that the ATP concentration in the mixed solution ofATP and substrate peptide (Caliper) was 50 uM.

As a result, some compounds of the present invention showed inhibitoryactivity against the kinase activity of ROS protein. Table 5 shows theIC₅₀ values obtained for some compounds of the present invention. Exdenotes Example No.

TABLE 5 Ex IC₅₀(nM) 565 0.40 566 0.86 567 0.23 568 1.0 569 0.65 570 0.51571 0.86 572 0.37 573 0.78 574 1.3 575 1.6 576 1.9 577 1.9 578 0.51 5790.58 580 0.29 581 0.41 582 1.2

ROS (v-Ros avian UR2 sarcoma virus oncogene homolog 1) is a receptortyrosine kinase and is a protein having a transmembrane region in themiddle part, flanked by a tyrosine kinase region on thecarboxyl-terminal side and an extracellular region on the amino-terminalside.

From the results of Test Example 6, it was confirmed that the compoundsof the present invention had inhibitory activity against the kinaseactivity of ROS protein. So far, as to the ROS gene, fusion with the FIGgene, the SLC34A2 gene, and the CD74 gene has been confirmed in cells orcancer tissue specimens derived from non-small cell lung cancers andglioblastoma (Biochimica et Biophysica Acta (BBA) Reviews on Cancer,2009, 1795, 37-52). Further, since it is known that siRNA which inhibitsmolecule expression of cell lines derived from SLC34A2-ROS fusionpolynucleotide-positive cancer patients shows an antitumor effect on thecell lines (Cell, 2007, 131, 1190-1203), it can be expected that acompound having inhibitory activity against the kinase activity of ROSprotein shows an antitumor effect on ROS fusion polynucleotide-positivecancer. These indicate that the compounds of the present invention areuseful as active ingredients in pharmaceutical compositions forpreventing and/or treating glioblastoma, such as ROS fusionpolynucleotide-positive cancer in one embodiment, ROS fusionpolynucleotide-positive lung cancer in another embodiment, ROS fusionpolynucleotide-positive non-small cell lung cancer in yet anotherembodiment, or ROS fusion polynucleotide-positive glioblastoma in yetanother embodiment.

Test Example 7 Evaluation of Inhibitory Activity Against the KinaseActivity of FLT3 Protein

A partial protein of only a kinase domain of FLT3 protein was purchasedfrom Carna Biosciences Inc., Japan, and tests were conducted as in TestExample 5.

As a result, some compounds of the present invention showed inhibitoryactivity against the kinase activity of FLT3 protein. Table 6 shows theIC₅₀ values obtained for some compounds of the present invention. Exdenotes Example No.

TABLE 6 Ex IC₅₀(nM) 565 0.44 566 0.51 567 0.46 568 0.50 569 0.35 5700.66 571 0.39 572 0.34 573 0.37 574 0.36 575 0.72 576 0.51 577 0.41 5780.56 579 0.36 580 0.49 581 0.52 582 0.37

FLT3 (Fms-like tyrosine kinase 3) is a receptor tyrosine kinase and is aprotein having a transmembrane region in the middle part, flanked by atyrosine kinase region on the carboxyl-terminal side and anextracellular region on the amino-terminal side.

From the results of Test Example 7, it was confirmed that the compoundsof the present invention had inhibitory activity against the kinaseactivity of FLT3 protein. So far, as to the FLT3 gene, active pointmutation and internal tandem duplication mutation in the juxtamembraneregion (FLT3-ITD) have been confirmed in cells derived from acutemyelocytic leukemia patients, and fusion with the SPTBN1 gene has beenconfirmed in cells derived from atypical chronic myelocytic leukemiapatients (active point mutation and internal tandem duplication in thejuxtamembrane region in acute myelocytic leukemia: CurrentPharmaceutical Design, 2005, 11, 3449-3457; fusion in atypical chronicmyelocytic leukemia: Experimental Hematology, 2007, 35, 1723-1727).Further, it is known that a compound having inhibitory activity againstthe kinase activity of FLT3 protein shows an antitumor effect on cellsderived from mutant FLT3 polynucleotide-positive cancer patients andcells derived from SPTBN1-FLT3 fusion polynucleotide-positive cancerpatients (Current Pharmaceutical Design, 2005, 11, 3449-3457;Experimental Hematology, 2007, 35, 1723-1727). These indicate that thecompounds of the present invention are useful as active ingredients inpharmaceutical compositions for preventing and/or treating acutemyelocytic leukemia, such as atypical chronic myelocytic leukemiapatients in one embodiment, mutant FLT3 polynucleotide-positive cancerin another embodiment, mutant FLT3 polynucleotide-positive acutemyelocytic leukemia in yet another embodiment, FLT3 fusionpolynucleotide-positive cancer in yet another embodiment, or FLT3 fusionpolynucleotide-positive atypical chronic myelocytic leukemia in yetanother embodiment.

Test Example 8 Kinase Inhibition Profiling

The inhibition rates against 78 types of tyrosine kinases (ABL, ARG,BTK, BMX, ITK, TEC, TXK, FRK, BLK, LCK, HCK, LYN, FGR, FYN, SRC, YES,BRK, SRM, CSK, CTK, FER, FES, ACK, TNK1, HER4, EGFR, HER2, JAK1, TYK2,JAK2, JAK3, ROS, ALK, LTK, IRR, INSR, IGF1R, DDR1, DDR2, MUSK, TRKA,TRKB, TRKC, TYRO3, AXL, MER, MET, RON, RET, FGFR4, FGFR1, FGFR2, FGFR3,FLT4, KDR, FLT1, FLT3, FMS, KIT, PDGFRa, PDGFRb, TIE2, EphA1, EphA2,EphA8, EphA7, EphA6, EphA4, EphA3, EphA5, EphB4, EphB3, EphB1, EphB2,FAK, PYK2, SYK, ZAP70) were calculated for each test compound at 5 nM.Activity measurement was made by Carna Biosciences Inc., Japan, and thedata were analyzed as follows: assuming that the average signal ofcontrol wells containing all reaction components was 0% inhibition andthe average signal in the absence of the enzyme was 100% inhibition, theinhibition rate was calculated for each test substance from the averagesignal of two test wells.

As a result, at a concentration of 5 nM, some compounds of the presentinvention showed 50% or more inhibitory activity against 7 types ofkinases including ALK, RET, ROS and FLT3 and, hence, appear to be highlyselective for specific kinases and to have fewer fears about safety,which fears are induced by inhibition of non-target kinases responsiblefor side effects.

A pharmaceutical composition which comprises one or more compounds offormula (I) or pharmaceutically acceptable salts thereof as an activeingredient can be prepared in a conventional manner by using apharmaceutical excipient, a pharmaceutical carrier or other additivescommonly used in the art.

Any mode of administration may be used, either oral administration inthe dosage form of tablets, pills, capsules, granules, powders,solutions or the like, or parenteral administration in the dosage formof injections (e.g., intraarticular, intravenous, intramuscular, and thelike), suppositories, eye drops, eye ointments, percutaneous solutions,ointments, percutaneous patches, transmucosal solutions, transmucosalpatches, inhalants or the like.

Solid compositions used for oral administration include tablets,powders, granules, and the like. In these solid compositions, one ormore active ingredients are mixed with at least one inert excipient, forexample, lactose, mannitol, glucose, hydroxypropylcellulose,microcrystalline cellulose, starch, polyvinylpyrrolidone, and/ormagnesium aluminometasilicate, or the like. The compositions may alsocomprise inert additives, for example, lubricants (e.g., magnesiumstearate and the like), disintegrating agents (e.g., carboxymethylstarch sodium and the like), stabilizers, and/or solubilizers, as in theusual cases. Tablets or pills may be coated with sugar coating or agastric or enteric film, if necessary.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs, or thelike, and comprise commonly-used inert diluents such as purified wateror ethanol. These liquid compositions may comprise, in addition to inertdiluents, auxiliaries (e.g., solubilizers, wetting agents, suspendingagents, and the like), sweeteners, flavors, aromatics, and/orantiseptics.

Injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions or emulsions. Examples of aqueoussolvents include injectable distilled water or physiological saline.Examples of non-aqueous solvents include propylene glycol, polyethyleneglycol or vegetable oils (e.g., olive oil and the like), as well asalcohols (e.g., ethanol and the like) or Polysorbate 80 (pharmacopoeianame), and the like. These compositions may further comprise isotonizingagents, antiseptics, wetting agents, emulsifiers, dispersants,stabilizers or solubilizers. They are sterilized, for example, byfiltration through a bacteria-retaining filter, by incorporation withdisinfectants or by irradiation. Alternatively, they may be formulatedinto a sterile solid composition and reconstituted for use by beingdissolved or suspended in sterile water or a sterile injectable solventbefore use.

Formulations for external use include ointments, plasters, creams,jellies, cataplasms, sprays, lotions, eye drops, eye ointments, and thelike. They comprise commonly-used ointment bases, lotion bases, aqueousor non-aqueous solutions, suspensions, emulsions or the like. Examplesof ointment or lotion bases include polyethylene glycol, propyleneglycol, white petrolatum, white beeswax, polyoxyethylene hydrogenatedcastor oil, glycerine monostearate, stearyl alcohol, cetyl alcohol,Lauromacrogol, sorbitan sesquioleate, and the like.

Transmucosal formulations such as inhalants or transnasal formulationsare used in solid, liquid or semi-solid form and can be prepared in aconventionally known manner. For example, such formulations may besupplemented as appropriate with known excipients and further with pHadjustors, antiseptics, surfactants, lubricants, stabilizers, thickenersand so on. For their administration, an appropriate device forinhalation or insufflation may be used. For example, using a knowndevice (e.g., a metered-dose inhalation device and the like) or anebulizer, the compound(s) may be administered alone or as a powder of aformulated mixture or as a solution or suspension in combination with apharmaceutically acceptable carrier. Dry powder inhalators or the likemay be for single or multiple administration use, and dry powders orpowder-containing capsules may be used in such devices. Alternatively,they may be in the form of pressurized aerosol sprays or the like whichuse an appropriate propellant, for example, a preferred gas such aschlorofluoroalkane, hydrofluoroalkane, carbon dioxide, or the like.

In general, for oral administration, the daily dosage is desirably about0.001 to 100 mg/kg, preferably 0.005 to 30 mg/kg, and more preferably0.01 to 10 mg/kg body weight, given as a single dose or in 2 to 4divided doses. For intravenous administration, the daily dosage isdesirably about 0.0001 to 10 mg/kg body weight, given in one or severaldoses per day. Likewise, for transmucosal formulations, the daily dosageis about 0.001 to 100 mg/kg body weight, given in one or several dosesper day. The dosage may be determined as appropriate for each case inconsideration of symptom, age, sex and so on.

The compounds of formula (I) can be used in combination with varioustherapeutic or prophylactic agents for diseases against which thecompounds of formula (I) would be effective. In general, when anantitumor agent is administered alone during chemotherapy for tumor,particularly malignant tumor, the antitumor agent has a limit in itseffect in terms of side effects and the like, and thus often fails toproduce a sufficient antitumor effect. For this reason, in clinicalcases, multidrug therapy is used in which two or more drugs withdifferent mechanisms of action are combined. By combining antitumoragents with different mechanisms of action, this combination therapyaims to reduce side effects and/or enhance the desired antitumor effect,for example, 1) to reduce the number of non-sensitive cell population,2) to prevent or delay the development of drug resistance, 3) todisperse toxicity by combination of drugs with different toxicitylevels, and the like. In such combination therapy, drugs may beadministered simultaneously or separately in succession or at desiredtime intervals. Formulations for simultaneous administration may be ineither mixed or separate form.

Drugs which can be combined include chemotherapeutics (e.g., alkylatingagent, antimetabolite, and the like), immunotherapeutic agents, hormonaltherapeutic agents, and cell growth factor inhibitors, more specificallydrugs such as cisplatin, carboplatin, paclitaxel, docetaxel,gemcitabine, irinotecan, vinorelbine, bevacizumab, pemetrexed and thelike.

EXAMPLES

How to prepare the compounds of formula (I) will be further explained inmore detail by way of the following examples. It should be noted thatthe present invention is not limited to the compounds shown in thefollowing examples. In addition, how to prepare the starting compoundsis shown in preparation examples. Processes for preparing the compoundsof formula (I) are not limited only to those actually shown in thefollowing examples, and the compounds of formula (I) may also beprepared by any combination of these processes or by any process obviousto those skilled in the art.

In the examples, preparation examples and tables shown below, thefollowing abbreviations are used as needed.

Rex: Preparation Example No., Ex: Example No., Structure: chemicalstructural formula, Data: physical and chemical data (FAB+:FAB-MS[M+H]⁺, ESI+: ESI-MS[M+H]⁺, APCI/ESI+: APCI/ESI-MS[M+H]+(APCI/ESImeans simultaneous measurement of APCI and ESI), FAB−: FAB-MS[M−H]⁻,ESI−: ESI-MS[M−H]⁻, APCI−: APCI-MS[M−H]⁻, ¹H-NMR (CDCl₃): δ(ppm) of¹H-NMR peaks in chloroform-d, ¹H-NMR (CD3OD): δ (ppm) of ¹H-NMR peaks inmethanol-d, ¹H-NMR (CDCl3+CD3OD): δ (ppm) of ¹H-NMR peaks in a mixedsolution of chloroform-d and methanol-d, ¹H-NMR (DMSO-d₆): δ (ppm) of¹H-NMR peaks in DMSO-d₆, XRD: diffraction angle) 2θ(°) of main peak inpowder X ray diffraction measurement, HCl: which means that the intendedproduct was obtained as hydrochloride, 2HCl: which means that theintended product was obtained as a dihydrochloride, TsOH: which meansthat the intended product was obtained as a p-toluene sulfonic acidsalt, HFM: which means that the intended product was obtained as ahemifumaric acid salt, FM: which means that the intended product wasobtained as a fumaric acid salt, Me: methyl, Et: ethyl, nPr:normalpropyl, iPr: isopropyl, cPr: cyclopropyl, cHex: cyclohexyl, Ph:phenyl, Bn: benzyl, Boc: tert-butyloxycarbonyl, Ac: acetyl. Syn:preparation process (indicating that the intended compound was preparedfrom corresponding starting materials as in the indicated PreparationExample or Example). In the Tables Shown in Preparation Examples orExamples, there are cis-trans isomers and their configurations areundecided, but as to compounds that show a single configuration of oneof cis and trans, no indication of configuration is made in theirchemical structural formulas and, instead, the symbol “*” is given totheir preparation example Nos. or example Nos. Compounds that are givethe same number following the symbol “*” indicate that one of thecompounds is a cis form and the other is a trans form.

The measurement of powder X ray diffraction was performed using RINT-TTRII under the following conditions; tube: Cu, tube current: 300 mA, tubevoltage: 50 kV, sampling width: 0.020°, scan rate: 4°/min, wavelength:1.54056 Å, range of diffraction angle measured (2θ): 2.5 to 40°. It isto be noted that the powder X ray diffraction should not strictly beunderstood, because, due to the nature of powder X ray diffraction data,crystal lattice space and overall pattern are important in determinationof crystal identity, and the relative intensity may vary in some degreedepending on the direction of crystal growth, particle size, andmeasurement conditions.

Preparation Example 4

A mixture of 4-methyl-3-nitrobenzoic acid (1.97 g) and thionyl chloride(6 mL) was heated under reflux for 18 hours. The reaction liquid wasconcentrated under reduced pressure, followed by an azeotropic processwith toluene to give a red-brown oil. To a mixture of the red-brown oiland THF (25 mL), diethylamine (2.6 mL) was added under ice cooling andstirred at room temperature for 5 hours. The reaction liquid was pouredinto water and extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure to give N,N-diethyl-4-methyl-3-nitrobenzamide (2.61 g)as a brown oil.

Preparation Example 41

To a mixture of 2-methoxy-4-nitrobenzenesulfonylchloride (600 mg) andTHF (5 mL), a mixture of piperidine (406 mg) and THF (1 mL) was addedand stirred at room temperature for 12 hours. After addition of 10%hydrochloric acid, the reaction liquid was extracted with ethyl acetate.The organic layer was washed with saturated aqueous sodium chloride andthen dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure to give1-[(2-methoxy-4-nitrophenyl)sulfonyl]piperidine (714 mg) as a yellowsolid.

Preparation Example 48

A mixture of 2-fluoro-5-nitrobenzoic acid (600 mg) and thionyl chloride(2 mL) was heated under reflux for 15 hours. The reaction liquid wasconcentrated under reduced pressure, followed by an azeotropic processwith toluene to give a yellow crystal. To a mixture of the yellowcrystal and THF (11 mL), triethylamine (0.47 mL) and isopropylamine(0.29 mL) were added under ice cooling and stirred at room temperaturefor 5 hours. The reaction liquid was poured into water and extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium chloride and then dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure to give a yellowcrystal. To a mixture of the yellow crystal (723 mg) and methanol (8 mL)and water (3 mL), ammonium chloride (2.05 g) and zinc powder (2.09 g)were added, and the mixture was heated under reflux for 3 hours. Afterfiltration of the reaction suspension through celite, the filtrate wasconcentrated under reduced pressure. The residue was poured intosaturated aqueous sodium hydrogen carbonate and extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride and then dried over anhydrous sodium sulfate, and the solventwas distilled off under reduced pressure. The residue was purified bysilica gel column chromatography (eluent; chloroform:methanol) to give5-amino-2-fluoro-N-isopropylbenzamide (527 mg) as a light brown crystal.

Preparation Example 160

To a mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (1.0 g) andDMF (15 mL), thionyl chloride (1 mL) was added at room temperature andstirred for 20 minutes. The reaction liquid was poured into ice-coldwater and extracted with ethyl acetate. The organic layer was washedwith saturated aqueous sodium chloride and then dried over anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(eluent; ethyl acetate:n-hexane) to give3,5-dichloro-6-ethylpyrazine-2-carbonitrile (608 mg) as a slightlyyellow oil.

Preparation Example 194

To a solution of a mixture of methyl5-chloro-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxylate(Preparation Example 193) (20 mg) and THF (2 mL), O-methylhydroxylaminehydrochloride (14 mg) was added. To the reaction liquid, lithiumhexamethyldisilazide (0.39 mL, 1M THF solution) was added under icecooling and stirred for 20 minutes. The reaction liquid was poured intosaturated aqueous sodium hydrogen carbonate and extracted with ethylacetate, and then the organic layer was washed with saturated aqueoussodium chloride. After drying over anhydrous sodium sulfate, the solventwas distilled off under reduced pressure to give5-chloro-N-methoxy-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide(21 mg) as a yellow powder.

Preparation Example 240

To a mixture of 1-(2-iodo-4-nitrophenyl)-4-methylpiperazine (PreparationExample 241) (406 mg), toluene (3 mL) and water (3 mL), sodium carbonate(496 mg), phenylboronic acid (157 mg) andtetrakis(triphenylphosphine)palladium (68 mg) were added in an argonatmosphere and stirred overnight at 110° C. The reaction liquid waspoured into water and extracted with ethyl acetate. The organic layerwas washed with saturated aqueous sodium chloride and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (eluent; chloroform/methanol) to give1-methyl-4-(5-nitrobiphenyl-2-yl)piperazine (348 mg) as a yellow brownoil.

Preparation Example 244

To a mixture of N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]acetamide(433 mg) and DMF (5 mL), 63% sodium hydride in oil (66 mg) was addedunder ice cooling and stirred at room temperature for 1 hour. Thereaction liquid was ice cooled again, and methyl iodide (0.11 mL) wasadded and stirred at room temperature for 4 hours. The reaction liquidwas poured into saturated aqueous ammonium chloride and extracted withethyl acetate. The organic layer was washed with saturated aqueoussodium chloride and then dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (eluent;chloroform:methanol) to giveN-methyl-N-[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]acetamide (200 mg)as an orange solid.

Preparation Example 246

To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (3.04 g) and THF(100 mL), ethyllithium (0.5 M benzene-cyclohexane solution) (56.8 mL)was added at −78° C. and stirred over 4 hours until it reached −50° C.After addition of water (150 mL), the reaction liquid was heated to roomtemperature and extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride and then dried over sodiumsulfate, and the solvent was distilled off. The resulting residue waspurified by silica gel column chromatography (eluent;chloroform:methanol=30:1) and further purified (eluent; n-hexane:ethylacetate=2:1 to 1:1) to give tert-butyl(4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 246) (0.202g), which was a low-polarity product, as a white solid and tert-butyl(4-ethyl-4-hydroxycyclohexyl)carbamate (Preparation Example 248), whichwas a high-polarity product, as a colorless syrup.

Preparation Example 247

To a mixture of tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate(Preparation Example 246) (0.202 g) and dioxane (2 mL), 26% hydrogenchloride-dioxane (1.1 mL) was added under ice cooling and stirred atroom temperature for 12 hours. The solvent was distilled off to give4-amino-1-ethylcyclohexanol hydrochloride (0.140 g) as a white viscoussolid.

Preparation Example 249

To a mixture of tert-butyl (4-ethyl-4-hydroxycyclohexyl)carbamate(Preparation Example 248) (0.256 g) and dioxane (2 mL), 26% hydrogenchloride-dioxane (1.4 mL) was added under ice cooling and stirred atroom temperature for 17 hours. The precipitated solid was collected byfiltration to give 4-amino-1-ethylcyclohexanol hydrochloride (0.152 g)as a white solid.

Preparation Example 250

To a mixture of tert-butyl (4-oxocyclohexyl)carbamate (3.04 g) and THF(100 mL), isopropyllithium (0.7 M pentane solution) (40.3 mL) was addedat −78° C. and stirred over 4 hours until it reached −50° C. Afteraddition of water (150 mL), the reaction liquid was heated to roomtemperature and extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride and then dried over sodiumsulfate, and the solvent was distilled off. The resulting residue waspurified by silica gel column chromatography (eluent; n-hexane:ethylacetate=3:1) and further purified (eluent; chloroform:methanol=30:1) togive tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (PreparationExample 250) (0.854 g), which was a low-polarity product, as a whitesolid and tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate(Preparation Example 252) (0.179 g), which was a high-polarity product,as a yellow oil.

Preparation Example 251

To a mixture of tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate(Preparation Example 250) (0.392 g) and dioxane (3 mL), 26% hydrogenchloride-dioxane (2.0 mL) was added under ice cooling and stirred atroom temperature for 18 hours. The precipitated solid was collected byfiltration to give 4-amino-1-isopropylcyclohexanol hydrochloride (0.190g) as a white solid.

Preparation Example 253

To a mixture of tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate(Preparation Example 252) (0.179 g) and dioxane (1.5 mL), 26% hydrogenchloride-dioxane (0.9 mL) was added under ice cooling and stirred atroom temperature for 18 hours. The precipitated solid was collected byfiltration to give 4-amino-1-isopropylcyclohexanol hydrochloride (0.086g) as a white solid.

Preparation Example 287

To a mixture of propane-2-thiol (3.30 mL), potassium carbonate (6.60 g)and DMF (40 mL), 1-fluoro-4-methyl-2-nitrobenzene (4.85 g) was added andstirred at room temperature for 5 hours. After addition of water, thereaction liquid was extracted with ethyl acetate, and the extract waswashed with water and saturated aqueous sodium chloride. After dryingover anhydrous sodium sulfate, the solvent was distilled off underreduced pressure to give 1-(isopropylsulfanyl)-4-methyl-2-nitrobenzene(6.60 g) as a yellow oil.

Preparation Example 291

To a mixture of 1-(isopropylsulfanyl)-4-methyl-2-nitrobenzene(Preparation Example 287) (6.60 g) and chloroform (150 mL),m-chloroperbenzoic acid (18.0 g) was added and stirred at 50° C. for 12hours. After the reaction liquid was cooled, saturated aqueous sodiumhydrogen carbonate and 5% aqueous sodium sulfite were added, and thereaction liquid was extracted with chloroform. After the organic layerwas dried over anhydrous sodium sulfate, the solvent was distilled offunder reduced pressure to give2-(isopropylsulfonyl)-4-methyl-1-nitrobenzene (7.41 g) as a yellowsolid.

Preparation Example 292

To a mixture of 2-(isopropylsulfonyl)-4-methyl-1-nitrobenzene(Preparation Example 291) (7.41 g) and acetic acid (70 mL), iron powder(5.43 g) was added and stirred at 80° C. for 3 hours. Thereafter,insoluble materials in the reaction liquid were removed, and the solventwas distilled off under reduced pressure. After addition of ethylacetate (150 mL) and removal of insoluble materials, the residue waswashed with water and saturated aqueous sodium chloride. After dryingover anhydrous sodium sulfate, the solvent was distilled off underreduced pressure. The residue was washed with ethyl acetate-diisopropylether to give 2-(isopropylsulfonyl)-4-methylaniline (3.86 g) as a lightyellow solid.

Preparation Example 298

To a mixture of 55% sodium hydride in oil (733 mg) and DMF (20 mL), amixture of 3-(methylsulfonyl)aniline (1.44 g) and THF (20 mL) were addedunder ice cooling and stirred for 30 minutes under ice cooling. Afterdropwise addition of a mixture of4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carboxamide (2.0 g) and DMF(30 mL) over 15 minutes, the reaction liquid was further stirred underice cooling for 15 minutes. After addition of 10% aqueous citric acid(300 mL) and extraction with ethyl acetate, the organic layer was washedwith saturated aqueous sodium chloride. After drying over anhydrousmagnesium sulfate, the solvent was concentrated, and the precipitatedsolid was collected by filtration and dried to give4-chloro-2-(methylsulfanyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide(1.95 g) as a light yellow solid.

Preparation Example 299

To a mixture of4-chloro-2-(methylsulfanyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide(Preparation Example 298) (1.95 g) and DMSO (30 mL), potassium carbonate(1.81 g) and 30% hydrogen peroxide solution (2.65 mL) were added andstirred at 50° C. for 1.5 hours. The reaction liquid was ice-cooled, and1M hydrochloric acid (25 mL) and thereafter water (150 mL) were addedand stirred for 30 minutes. The precipitated solid was collected byfiltration and washed with water to give2-(methylsulfanyl)-4-{[3-(methylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide(1.40 g) as a light yellow solid.

Preparation Example 304

To a mixture of4-chloro-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide(Preparation Example 303) (51 mg) and methanol (1 mL), sodium methoxide(11 mg) was added under ice cooling and stirred overnight at roomtemperature. Water was added to the reaction liquid, and the solid wascollected by filtration to give4-methoxy-6-[(6-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide(41 mg).

Preparation Example 311

To a mixture of4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide(Preparation Example 306) (500 mg), dichloromethane (40 mL) and methanol(40 mL), a mixture of Oxone® (922 mg) and water (10 mL) was added andstirred at room temperature for 18 hours. To the reaction liquid,chloroform and water were added, and the precipitated solid wascollected by filtration and washed with water to give4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfinyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide(234 mg) as a light yellow solid.

Preparation Example 339

To a mixture of4-methoxy-6-[(6-methoxy-pyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide(Preparation Example 337) (0.35 g) and water (2.2 mL), concentratedhydrochloric acid (2.2 mL) was added and stirred at 80° C. for 1.5hours. After the reaction liquid was cooled, 1M aqueous sodium hydroxidewas added so that the reaction liquid became almost neutral, and thenthe resulting solid was collected by filtration to give4-[(6-methoxy-pyridin-3-yl)amino]-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide(0.34 g).

Preparation Example 342

To a mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine-5-carboxylicacid (1.50 g) and dichloromethane (15 mL), oxalyl chloride (1.20 mL) andDMF (0.015 mL) were added under ice cooling and stirred 30 minutes underice cooling and 2 hours at room temperature. The solvent was distilledoff under reduced pressure, followed by an azeotropic process withtoluene. The resulting residue was dissolved in THF, followed bydropwise addition of 40% aqueous methylamine at −10° C. After thedropwise addition was completed, the reaction liquid was concentrated,and water was added. The resulting solid was collected by filtration andwashed with water to give a white solid. The solid was dissolved inethyl acetate, washed with saturated aqueous sodium chloride, and thendried over anhydrous magnesium sulfate. The solvent was distilled off.To a mixture of the resulting residue and dioxane (20 mL),3-(methylsulfonyl)aniline hydrochloride (432 mg) andN,N-diisopropylethylamine (0.73 mL) were added and stirred at 100° C.for 4 hours. After cooling, the reaction liquid was diluted with ethylacetate and washed with saturated aqueous sodium chloride. After dryingover anhydrous magnesium sulfate, the solvent was distilled off, and theresidue was purified by silica gel column chromatography (eluent;chloroform:methanol=100:0 to 30:1) to give4-chloro-N-methyl-2-(methylsulfanyl)-6-{[3-(methylsulfonyl)phenyl]amino}pyrimidine-5-carboxamide(445 mg) as a white solid.

Preparation Example 346

To a mixture of4-chloro-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidine-5-carboxamide(Preparation Example 344) (0.68 g) and sodium acetate (0.80 g), DMF (7mL) was added and stirred at 100° C. for 6 hours. After the reactionliquid was returned to room temperature, water was added, and theresulting solid was collected by filtration to give5-carbamoyl-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidin-4-ylacetate (0.71 g).

Preparation Example 349

To 5-carbamoyl-2-(methylsulfanyl)-6-(quinolin-3-ylamino)pyrimidin-4-ylacetate (Preparation Example 346) (0.71 g), ethanol (14 mL) and THF (14mL) were added, and 1M aqueous sodium hydroxide (6 mL) was added andstirred at room temperature for 1 hour. Then, 1M hydrochloric acid (6mL) was added, and the precipitated solid was collected by filtrationand dried to give2-(methylsulfanyl)-6-oxo-4-(quinolin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamide(0.63 g).

Preparation Example 353

A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (600 mg),3-(methylsulfonyl)aniline (467 mg), N,N-diisopropylethylamine (0.48 mL)and dioxane (18 mL) was stirred in a sealed tube at 170° C. for 17hours. After cooling, the mixture was partitioned using ethyl acetateand water, and the organic layer was washed with saturated aqueoussodium chloride and then dried over anhydrous magnesium sulfate. Afterthe solvent was distilled off, the residue was washed with chloroform,and the solid was collected by filtration and dried to give5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(412 mg) as a yellow solid.

Preparation Example 364

To a mixture of4-chloro-6-[(5-methylpyridin-3-yl)amino]-2-(methylsulfanyl)pyrimidine-5-carboxamide(Preparation Example 359) (194 mg) and DMF (5 mL), sodium acetate (257mg) was added and stirred at 100° C. for 5 hours. After the reactionliquid was cooled, ethyl acetate and water were added, and theprecipitated powder was collected by filtration and dried to give alight yellow solid. To a mixture of the solid, ethanol (5 mL), methanol(20 mL) and THF (5 mL), 1M aqueous sodium hydroxide (3 mL) was added andstirred at room temperature for 1 hour, at 60° C. for 1 hour, and at 80°C. for 1 hour. After the reaction liquid was cooled, 1M hydrochloricacid (3 mL) was added, and the reaction liquid was extracted withchloroform-isopropanol. Silica gel was added to the organic layer, andthe solvent was distilled off, followed by purification by silica gelcolumn chromatography (eluent; chloroform:methanol=100:0 to 20:1) togive a crude product. This crude product was washed with a small amountof methanol to give4-[(5-methylpyridin-3-yl)amino]-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide(27 mg) as a yellow solid.

Preparation Example 397

To a mixture of5-chloro-6-ethyl-3-{[4-(methylsulfanyl)phenyl]amino}pyrazine-2-carboxamide(Preparation Example 394) (92 mg) and acetic acid (2.5 mL), sodiumtungstate dihydrate (29 mg) and 30% hydrogen peroxide solution (0.15 mL)were added and stirred at room temperature for 30 minutes. After waterand ethyl acetate were added to the reaction liquid, 1M aqueous sodiumhydroxide was added and stirred for 30 minutes, and the reaction liquidwas partitioned. After drying over anhydrous sodium sulfate, the organiclayer was filtered and concentrated. The resulting residue was washedwith ethyl acetate to give5-chloro-6-ethyl-3-{[4-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(103 mg).

Preparation Example 398

To a mixture of3,5-dichloro-6-(1-hydroxy-1-methylethyl)pyrazine-2-carboxamide (2.64 g)and pyridine (30 mL), mesyl chloride (2.45 mL) was added under icecooling. After stirring at room temperature for 5 hours, pyridine wasdistilled off under reduced pressure, and the resulting residue waspartitioned using ethyl acetate and water. The resulting organic layerwas washed with 10% aqueous citric acid, saturated aqueous sodiumhydrogen carbonate and saturated aqueous sodium chloride, and dried overanhydrous magnesium sulfate, and the solvent was distilled off to give alight brown syrup. To the light brown syrup, ethanol (60 mL) and THF (30mL) were added, and then 10% palladium on carbon (0.7 g) was added andstirred at room temperature for 14 hours under 3 atmospheric pressure ofhydrogen. After filtration through celite, the filtrate was distilledoff under reduced pressure, and the residue was diluted with ethylacetate and then washed with saturated aqueous sodium hydrogen carbonateand saturated aqueous sodium chloride. After the solvent was distilledoff, the residue was purified by silica gel column chromatography(eluent; chloroform:methanol=100:0 to 40:1). The resulting crude productwas washed with diisopropyl ether to give3,5-di-chloro-6-isopropylpyrazine-2-carboxamide (632 mg) as a whitesolid.

Preparation Example 399

To a mixture of tert-butyl (1-methyl-4-oxocyclohexyl)carbamate (4.00 g)and methanol (50 mL), ammonium formate (10.2 g) and water (5 mL) wereadded and stirred for 1 hour until they were completely dissolved. Then,10% palladium on carbon (2.0 g) was added and stirred at roomtemperature for 65 hours. After insoluble materials were separated byfiltration through celite, the solvent was distilled off, and chloroformwas added to the resulting residue, followed by drying over anhydrousmagnesium sulfate. The solvent was distilled off to give tert-butyl(4-amino-1-methylcyclohexyl)carbamate (3.73 g) as a colorless syrup.

Preparation Example 400

To a mixture of tert-butyl (4-amino-1-methylcyclohexyl)carbamate(Preparation Example 399) (3.73 g) and ethanol (30 mL), 4M hydrogenchloride in ethyl acetate (30 mL) was added under ice cooling andstirred at room temperature for 20 hours. The precipitated solid wascollected by filtration and washed with ethyl acetate to give1-methylcyclohexane-1,4-diamine dihydrochloride (2.10 g) as a whitesolid.

Preparation Example 412

To a mixture of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(3.16 g), 4-bromo-3-methoxy-1-nitrobenzene (2.63 g) and DMF (31.6 mL),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane adduct (0.50 g) and potassium carbonate (4.24 g) wereadded and stirred at 80° C. for 4 hours. After this mixture wasconcentrated under reduced pressure, water and ethyl acetate were added,and insoluble materials were filtered through celite. The organic layerwas washed with saturated aqueous sodium chloride. After drying overanhydrous magnesium sulfate, the solvent was distilled off, and theresidue was purified by silica gel column chromatography (eluent;n-hexane:ethyl acetate=1:0 to 2:1) to give tert-butyl4-(2-methoxy-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.21g) as a yellow solid.

Preparation Example 413

To a mixture of tert-butyl4-(2-methoxy-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate(Preparation Example 412) (2.21 g), ethanol (40 mL) and THF (20 mL), 10%palladium on carbon (1.0 g) was added and stirred at room temperaturefor 3 hours under a hydrogen atmosphere at normal pressure. Afterfiltration through celite, the filtrate was distilled off under reducedpressure to give tert-butyl4-(4-amino-2-methoxy-phenyl)piperidine-1-carboxylate (1.97 g) as a graysolid.

Preparation Example 417

A mixture of5-chloro-6-(1-hydroxy-1-methylethyl)-3-{[4-(4-methylpyrazin-1-yl)phenyl]amino}pyrazine-2-carboxamide(Preparation Example 416) (430 mg) and acetic acid (10 mL) was stirredat 120° C. for 5 hours. After the reaction liquid was cooled, thesolvent was distilled off, and water and saturated aqueous sodiumhydrogen carbonate were added to neutralize. After extraction with ethylacetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride and dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waswashed with diisopropyl ether to give5-chloro-6-isopropenyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide(265 mg) as an orange solid.

Preparation Example 430

To a mixture of 7-nitro-2H-1,4-benzoxazine-3(4H)-one (2.0 g),benzyltriethylammonium chloride (470 mg), potassium carbonate (4.27 g)and acetonitrile (60 mL), 1-bromo-2-chloroethane (1.28 mL) was added andstirred at 75° C. for 3 hours. After the reaction liquid was cooled,saturated aqueous sodium hydrogen carbonate was added, and the reactionliquid was extracted with ethyl acetate and the extract was washed withsaturated aqueous sodium chloride. After drying over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent:chloroform) to give4-(2-chloroethyl)-7-nitro-2H-1,4-benzoxazine-3(4H)-one (1.92 g) as ayellow powder.

Preparation Example 432

To a mixture of 4-(2-chloroethyl)-7-nitro-2H-1,4-benzoxazine-3(4H)-one(Preparation Example 430) (1.08 g), potassium carbonate (0.87 g) andacetonitrile (10.8 mL), 1-methylpiperazine (1.39 mL) was added andstirred at 80° C. for 48 hours. After the reaction liquid was cooled,saturated aqueous sodium hydrogen carbonate was added, and the reactionliquid was extracted with ethyl acetate and the extract was washed withsaturated aqueous sodium chloride. After drying over anhydrous magnesiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent;chloroform:methanol=100:0 to 20:1) to give4-[2-(4-methylpiperazin-1-yl)ethyl]-7-nitro-2H-1,4-benzoxazine-3(4H)-one(690 mg) as a yellow liquid.

Preparation Example 440

A mixture of3,5-dichloro-6-(1-hydroxy-1-methylethyl)pyrazine-2-carboxamide (1.10 g),4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)aniline(Preparation Example 436) (1.58 g), N,N-diisopropylethylamine (0.80 mL)and dioxane (31 mL) was stirred at 100° C. for 135 hours. After cooling,water was added, followed by extraction with ethyl acetate. Further,insoluble materials were separated by filtration, and the insolublematerials were dissolved in methanol and thereafter mixed with theorganic layer. The solvent was distilled off under reduced pressure,followed by drying to give a brown solid. A mixture of the brown solidand acetic acid (30 mL) was stirred at 120° C. for 5 hours. After thesolvent was distilled off, saturated aqueous sodium hydrogen carbonatewas added, and the precipitated solid was collected by filtration andwashed with water. The resulting solid was purified by basic silica gelcolumn chromatography (eluent: chloroform) to give5-chloro-6-isopropenyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide(0.99 g) as a yellow solid.

Preparation Example 444

After a mixture of palladium acetate (188 mg),1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (781 mg), cesiumcarbonate (4.09 g) and THF (20 mL) was stirred for 30 minutes, a mixtureof 1-bromo-3-methoxy-5-nitrobenzene (1.94 g), 1-methylpiperazine (2.76mL) and THF (20 mL) was added and heated under reflux for 14 hours.After cooling, the reaction liquid was diluted with ethyl acetate, andinsoluble materials were separated by filtration. After extraction with2M hydrochloric acid from the filtrate, the resulting aqueous layer wasbasified with 50% aqueous potassium hydroxide and then extracted withchloroform. After the organic layer was dried over anhydrous magnesiumsulfate, the solvent was distilled off, and the residue was purified bysilica gel column chromatography (eluent; chloroform:methanol=100:0 to20:1) to give 1-(3-methoxy-5-nitrophenyl)-4-methylpiperazine (1.01 g) asan orange syrup.

Preparation Example 454

To a mixture of tert-butyl4-(4-amino-2-methoxy-phenyl)piperidine-1-carboxylate (PreparationExample 413) (4.25 g) and THF (100 mL), sodium hydrogen carbonate (1.28g) and water (30 mL) were added, followed by dropwise addition of benzylchloroformate (1.98 mL) under ice cooling and stirring overnight. Afteraddition of water and extraction with ethyl acetate, the extract waswashed with saturated aqueous sodium chloride. After drying overanhydrous magnesium sulfate, the solvent was distilled off, and theresidue was purified by silica gel column chromatography (eluent;n-hexane:ethyl acetate=2:1) to give tert-butyl4-(4-{[(benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate(4.92 g) as a colorless amorphous.

Preparation Example 455

A mixture of tert-butyl4-(4-{[(benzyloxy)carbonyl]amino}-2-methoxyphenyl)piperidine-1-carboxylate(Preparation Example 454) (4.92 g), trifluoroacetic acid (10 mL) and1,2-dichloroethane (50 mL) was stirred at room temperature for 1 hour.The reaction solvent was concentrated under reduced pressure, and afteraddition of saturated aqueous sodium hydrogen carbonate, the residue wasextracted with chloroform. After drying over anhydrous magnesiumsulfate, the solvent was distilled off, and the residue was solidifiedby addition of diethyl ether to give benzyl(3-methoxy-4-piperidin-4-ylphenyl)carbamate (3.24 g) as a white solid.

Preparation Example 464

To a mixture of benzyl (3-methoxy-4-piperidin-4-ylphenyl)carbamate(Preparation Example 455) (1.52 g) and 1,2-dichloroethane (70 mL),formalin (3.62 mL) and sodium triacetoxyborohydride (1.42 g) were addedand stirred overnight at room temperature. After addition of water andsaturated aqueous sodium hydrogen carbonate, the reaction liquid wasextracted with chloroform, and the organic layer was dried overanhydrous magnesium sulfate. After the solvent was distilled off underreduced pressure, the residue was purified by silica gel columnchromatography (eluent; chloroform:methanol:saturated aqueousammonia=100:0:0 to 10:1:0.1) to give benzyl[3-methoxy-4-(1-methylpiperidin-4-yl)phenyl]carbamate (1.26 g) as awhite solid.

Preparation Example 467

To a mixture of7-amino-4-[3-(4-methylpiperazin-1-yl)propyl]-2H-1,4-benzoxazine-3(4H)-one(Preparation Example 435) (300 mg) and THF (9 mL), gradual dropwiseaddition of borane-tetrahydrofuran complex (3.0 mL, 1M THF solution) wasconducted under ice cooling under an argon atmosphere. After thedropwise addition was completed, the mixture was stirred at roomtemperature for 1 hour and further stirred at 70° C. for 3 hours. Aftermethanol (10 mL) was gradually added to the reaction liquid under icecooling, 1M hydrochloric acid (5 mL) and thereafter 1M aqueous sodiumhydroxide (10 mL) were added and stirred at room temperature for 1 hour.After dilution with water, the reaction liquid was extracted with ethylacetate. After the solvent was distilled off, the residue was purifiedby silica gel column chromatography (eluent; chloroform:methanol=100:0to 20:1) to give4-[3-(4-methylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazine-7-amine(120 mg).

Preparation Example 468

To a mixture of benzyl[3-methoxy-4-(1-methylpiperidin-4-yl)phenyl]carbamate (PreparationExample 464) (1.26 g), ethanol (20 mL) and THF (10 mL), 5% palladium oncarbon (0.38 g) was added and stirred overnight at room temperatureunder a hydrogen atmosphere at normal pressure. After filtration throughcelite, the filtrate was distilled off under reduced pressure to give3-methoxy-4-(1-methylpiperidin-4-yl)aniline (0.80 g) as a light pinksolid.

Preparation Example 472

To a mixture of 2-[methyl(3-nitrophenyl)amino]ethanol (780 mg) anddichloromethane (20 mL), triethylamine (0.66 mL) and mesyl chloride(0.37 mL) were added sequentially under ice cooling and stirred for 3hours. Water was added to the reaction liquid, and the organic layer wasseparated and washed with saturated aqueous sodium chloride. Afterdrying over anhydrous magnesium sulfate, the solvent was distilled offto give 2-[methyl(3-nitrophenyl)amino]ethyl methanesulfonate (1.0 g) asa yellow solid.

Preparation Example 473

A mixture of 2-[methyl(3-nitrophenyl)amino]ethyl methanesulfonate(Preparation Example 472) (1.0 g), 1-methylpiperazine (1.61 mL) and NMP(5 mL) was reacted at 130° C. for 30 minutes using a microwave reactionsystem. The reaction liquid was diluted with water, extracted with amixed solvent of chloroform and methanol (10:1), and then washed withsaturated aqueous sodium chloride. After drying over anhydrous magnesiumsulfate, the solvent was distilled off, and the residue was purified bysilica gel column chromatography (eluent; chloroform:methanol:saturatedaqueous ammonia=10:1:0.1) to giveN-methyl-N-[2-(4-methylpiperazin-1-yl)ethyl]-3-nitroaniline (890 mg) asa yellow oil.

Preparation Example 502

To a mixture of8-(2-methoxy-5-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (PreparationExample 495) (795 mg) and dioxane (16 mL), 4M hydrochloric acid (6.8 mL)was added and stirred overnight at 80° C. The reaction liquid wasconcentrated under reduced pressure, and saturated aqueous sodiumhydrogen carbonate was added to the concentrate. The concentrate wasextracted with chloroform and then washed with saturated aqueous sodiumchloride. After drying over anhydrous sodium sulfate, the solvent wasdistilled off under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent; ethyl acetate:n-hexane) togive 1-(2-methoxy-5-nitrophenyl)piperidin-4-one (296 mg).

Preparation Example 503

To a mixture of 1-(2-methoxy-5-nitrophenyl)piperidin-4-one (PreparationExample 502) (296 mg), 1-methylpiperazine (0.20 mL) and1,2-dichloroethane (11 mL), sodium triacetoxyborohydride (385 mg) wasadded and stirred overnight at room temperature. After addition of waterand saturated aqueous sodium hydrogen carbonate, the reaction liquid wasextracted with chloroform, and the organic layer was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent: chloroform:methanol=100:0 to 10:1) to give1-[1-(2-methoxy-5-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (0.40g) as a brown oil.

Preparation Example 516

To a mixture of 1-fluoro-2-methyl-4-nitrobenzene (3.0 g), potassiumcarbonate (5.35 g) and DMF (30 mL), 1,4-dioxa-8-azaspiro[4.5]decane(4.15 g) was added and stirred at 80° C. for 20 hours. After cooling,the reaction liquid was diluted with ethyl acetate and washed with waterand saturated aqueous sodium chloride. After drying over anhydrousmagnesium sulfate, the solvent was distilled off, and the residue waspurified by silica gel column chromatography (eluent;chloroform:methanol=100:0 to 100:1) to give8-(2-methyl-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane (5.13 g) as ayellow solid.

Preparation Example 545

To a mixture of5-chloro-6-(2-hydroxypropan-2-yl)-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide(Preparation Example 544) (300 mg) and trifluoroacetic acid (3 mL),triethylsilane (0.55 mL) was added under ice cooling and stirred underice cooling for 10 minutes and at room temperature for 22 hours. Afterthe reaction liquid was concentrated, the residue was diluted withchloroform and washed with saturated aqueous sodium hydrogen carbonate.After drying over anhydrous magnesium sulfate, the solvent was distilledoff, and the residue was purified by silica gel column chromatography(eluent; chloroform:methanol:saturated aqueous ammonia=100:0:0 to20:1:0.1) to give a crude product. The crude product was washed withdiisopropyl ether to give5-chloro-6-isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide(219 mg) as an orange solid.

Tables 7 to 47 show the chemical structures of the compounds prepared inthe above preparation examples, and the chemical structures of thecompounds of preparation examples prepared by the same manner as shownin the above preparation examples using corresponding startingmaterials. Tables 48 to 84 show the preparation processes and physicaland chemical data of these preparation examples compounds.

Example 4

A mixture of4-{[2-(isopropylsulfonyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide(Preparation Example 294) (200 mg),1-(aminomethyl)-N,N-dimethylcyclohexylamine (409 mg) and NMP (1 mL) washeated at 180° C. for 10 minutes using a microwave reaction system.After cooling, the reaction liquid was diluted with ethyl acetate, andthe precipitated crystal was collected by filtration and washed withethyl acetate to give a white solid. To the white solid, a mixed solventof ethanol and water was added, heated and then cooled, and theprecipitated solid was collected by filtration to give2-({[1-(dimethylamino)cyclohexyl]methyl}amino)-4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide(136 mg) as a white solid.

Example 19

A mixture of4-{[2-(isopropylsulfonyl)phenyl]amino}-2-(methylsulfanyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide(Preparation Example 294) (200 mg), tert-butyl2-(aminomethyl)piperidine-1-carboxylate (1.12 g) and NMP (1 mL) washeated at 180° C. for 10 minutes using a microwave reaction system.After cooling, the reaction liquid was diluted with ethyl acetate andwashed with water and saturated aqueous sodium chloride. After dryingover anhydrous magnesium sulfate, the solvent was distilled off, and theresidue was purified by silica gel column chromatography(chloroform:methanol=100:0 to 20:1) to give a white amorphous. To amixture of the white amorphous, ethyl acetate (10 mL) and ethanol (5mL), 4M hydrogen chloride in ethyl acetate (5 mL) was added under icecooling and stirred at room temperature for 4 hours. The precipitatedsolid was collected by filtration and dried to give4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-[(piperidin-2-ylmethyl)amino]-1,6-dihydropyrimidine-5-carboxamidehydrochloride (126 mg) as a white solid.

Example 29

To a mixture of tert-butyl3-[(5-carbamoyl-4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-2-yl)amino]piperidine-1-carboxylate(Example 28) (299 mg) and ethyl acetate (3 mL), 4M hydrogen chloride inethyl acetate (2.7 mL) was added under ice cooling and stirred at roomtemperature for 1 hour. The precipitated solid was collected byfiltration and dried to give4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-(piperidin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamidedihydrochloride (194 mg) as a white solid.

Example 31

To a mixture of4-{[2-(isopropylsulfonyl)phenyl]amino}-6-oxo-2-(piperidin-3-ylamino)-1,6-dihydropyrimidine-5-carboxamidedihydrochloride (Example 29) (67 mg) and pyridine (1.3 mL), mesylchloride (0.10 mL) was added under ice cooling and stirred for 1 hour.After ethanol was added to the reaction system, the reaction system wasconcentrated. The resulting residue was partitioned using chloroform andsaturated aqueous sodium hydrogen carbonate, and the organic layer wasdried. The organic layer was concentrated, followed by an azeotropicprocess with toluene. The resulting residue was solidified with ethylacetate-hexane. The resulting solid was recrystallized from ethanol togive4-{[2-(isopropylsulfonyl)phenyl]amino}-2-{[1-(methylsulfonyl)piperidin-3-yl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide(43 mg).

Example 37

A mixture of4-{[3-(methylcarbamoyl)phenyl]amino}-2-(methylsulfinyl)-6-oxo-1,6-dihydropyrimidine-5-carboxamide(Preparation Example 311) (234 mg), 1-(aminomethyl)cyclohexaneamine (172mg) and NMP (2 mL) was stirred at 80° C. for 30 minutes. After cooling,the reaction liquid was diluted with ethyl acetate, and the precipitatedsolid was collected by filtration. This solid was heated withethanol-water and washed to give2-{[(1-aminocyclohexyl)methyl]amino}-4-{[3-(methylcarbamoyl)phenyl]amino}-6-oxo-1,6-dihydropyrimidine-5-carboxamide(215 mg) as a white solid.

Example 84

A mixture of5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(Preparation Example 353) (150 mg), 1-(aminomethyl)cyclohexaneamine (163mg) and NMP (1 mL) was heated at 180° C. for 20 minutes using amicrowave reaction system. The reaction liquid was cooled, and ethylacetate and water were added and stirred for 30 minutes. Thereafter, theprecipitated powder was collected by filtration. This powder was heatedwith ethanol-water (1:1) and washed to give5-{[(1-aminocyclohexyl)methyl]amino}-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(112 mg) as a white solid.

Example 146

A mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (200 mg),3-chloro-4-methylsulfonylaniline (374 mg) and NMP (1 mL) was stirred at230° C. for 1 hour using a microwave reaction system. Thereafter,trans-4-aminocyclohexanol (524 mg) was added to the reaction liquid andstirred at 190° C. for 30 minutes using a microwave reaction system.After cooling, the reaction liquid was partitioned using ethyl acetateand water, and the organic layer was washed with saturated aqueoussodium hydrogen carbonate and saturated aqueous sodium chloride. Afterdrying over anhydrous magnesium sulfate, the solvent was distilled off,and the residue was purified by silica gel column chromatography(eluent; chloroform:methanol=10:0 to 30:1) to give a crude product. Thisproduct was heated with ethanol and washed to give a light yellow solid.To the light yellow solid, ethyl acetate was added and heated, andinsoluble materials were separated by filtration and the filtrate wasconcentrated. After the filtrate was concentrated, the residue washeated and washed with ethanol to give3-{[3-chloro-4-(methylsulfonyl)phenyl]amino}-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide(39 mg) as a light yellow solid.

Example 159

To a mixture of5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(Example 111) (298 mg), chloroform (40 mL) and acetonitrile (10 mL),N-chlorosuccinimide (108 mg) was added and stirred at 70° C. for 8hours. After the reaction liquid was cooled, silica gel was added, andthe solvent was distilled off, followed by purification by silica gelcolumn chromatography (eluent; chloroform:methanol=10:0 to 10:1). Theresulting crude product was solidified from chloroform and collected byfiltration. The resulting solid was heated with ethyl acetate and washedwith ethyl acetate to give6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(189 mg) as a white solid.

Example 181

To a mixture of5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(Example 111) (150 mg), chloroform (40 mL) and acetonitrile (20 mL),N-bromosuccinimide (69 mg) was added and stirred at room temperature for2 hours. To the reaction liquid, silica gel was added, and the solventwas distilled off, followed by purification by silica gel columnchromatography (eluent; chloroform:methanol=10:0:0 to 10:1). Theresulting crude product was solidified with ethyl acetate and washedwith ethyl acetate to give6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(130 mg) as a light yellow solid.

Example 190

To a mixture of5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(Example 111) (150 mg), chloroform (40 mL) and acetonitrile (20 mL),N-iodosuccinimide (87 mg) was added and stirred at room temperature for2 hours. To the reaction liquid, silica gel was added, and the solventwas distilled off, followed by purification by silica gel columnchromatography (eluent; chloroform:methanol=10:0 to 10:1). The resultingcrude product was solidified with ethyl acetate and washed with ethylacetate to give5-[(trans-4-hydroxycyclohexyl)amino]-6-iodo-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(153 mg) as a light yellow solid.

Example 196

A mixture of5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(Preparation Example 353) (8.8 mg), 1-methyl-piperidin-3-ylamine (8.0mg) and NMP (0.5 mL) was heated at 190° C. for 30 minutes using amicrowave reaction system. After the reaction liquid was cooled, theorganic layer was distilled off under reduced pressure, and the residuewas separated and purified by HPLC (column: SunFire® C18, 5 μm, 19mm×100 mm, solvent: MeOH/0.1% HCOOH—H₂O=10/90 (0 min)-10/90 (1 min)-95/5(9 min)-95/5 (12 min), flow rate: 25 mL/min) to give(6-ethyl-5-[(1-methylpiperidin-3-yl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(2.4 mg).

Example 302

To a mixture of5-[(4-amino-4-methylcyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}-6-propylpyrazine-2-carboxamide(Example 301) (89 mg) and dichloromethane (5 mL), formalin (0.30 mL) andsodium triacetoxyborohydride (82 mg) were added and stirred at roomtemperature for 1.5 hours. After the reaction liquid was diluted withchloroform, it was washed with saturated aqueous sodium hydrogencarbonate and dried over anhydrous magnesium sulfate. After the dryingagent was separated by filtration, silica gel was added, and the solventwas distilled off, followed by purification of the residue by silica gelcolumn chromatography (eluent; chloroform:methanol:saturated aqueousammonia=10:0:0 to 10:1:0.1). The resulting residue was washed with ethylacetate to give5-{[4-(dimethylamino)-4-methylcyclohexyl]amino}-3-{[3-(methylsulfonyl)phenyl]amino}-6-propylpyrazine-2-carboxamide(31 mg) as a light yellow solid.

Example 309

To a mixture of6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-[(4-methyl-3-nitrophenyl)amino]pyrazine-2-carboxamide(Example 308) (242 mg) and methanol (10 mL), 5% palladium on carbon (25mg) was added and stirred under a hydrogen atmosphere at roomtemperature for 4 hours. After filtration of the reaction liquid, thefiltrate was concentrated under reduced pressure to give3-[(3-amino-4-methylphenyl)amino]-6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]pyrazine-2-carboxamide(162 mg) as a green solid.

Example 310

To a mixture of3-[(3-amino-4-methylphenyl)amino]-6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]pyrazine-2-carboxamide(Example 309) (150 mg), THF (2 mL) and DMF (2 mL),N,N-diisopropylethylamine (49 mg) and acrylic acid chloride (34 mg) wereadded under ice cooling and stirred for 30 minutes. The reaction liquidwas poured into water and extracted with ethyl acetate. The organiclayer was washed with water and saturated aqueous sodium chloridesequentially and then dried over anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (eluent;chloroform:methanol) to give3-{[3-(acryloylamino)-4-methylphenyl]amino}-6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]pyrazine-2-carboxamide(48 mg) as a light yellow powder.

Example 343

To a mixture of5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropenyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide(Example 342) (205 mg), ethanol (20 mL) and THF (10 mL), 10% palladiumon carbon (100 mg) was added under a hydrogen atmosphere and stirred atroom temperature for 18 hours. After the catalyst was separated byfiltration, the solvent was distilled off, and the residue was purifiedby basic silica gel column chromatography (eluent: chloroform). Theresulting yellow solid was washed with ethyl acetate to give5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide(136 mg) as a yellow solid.

Example 381

To a mixture of tert-butyl4-[4-({3-carbamoyl-5-ethyl-6-[(trans-4-hydroxycyclohexyl)amino]pyrazin-2-yl}amino)-2-methoxyphenyl]piperidine-1-carboxylate(Example 382) (270 mg) and ethyl acetate (10 mL), 4M hydrogen chloridein ethyl acetate (4 mL) was added under ice cooling and stirred at roomtemperature for 1 hour. The reaction liquid was concentrated underreduced pressure, and saturated aqueous sodium hydrogen carbonate andchloroform were added to the residue. The precipitated solid wascollected by filtration and dried to give6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(3-methoxy-4-piperidin-4-ylphenyl)amino]pyrazine-2-carboxamide(85 mg) as a light yellow solid.

Example 405

To a mixture of6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-[(4-piperidin-4-ylphenyl)amino]pyrazine-2-carboxamide(Example 358) (43 mg) and dichloroethane (1 mL), pyridine (0.01 mL) andacetic anhydride (0.01 mL) were added under ice cooling and stirred atroom temperature for 20 minutes. After addition of saturated aqueoussodium hydrogen carbonate, the reaction liquid was partitioned usingchloroform and saturated aqueous sodium hydrogen carbonate. After dryingover anhydrous sodium sulfate, the organic layer was concentrated, andthe resulting residue was solidified with ethyl acetate-hexane to give3-{[4-(1-acetylpiperidin-4-yl)phenyl]amino}-6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide(26 mg) as a white solid.

Example 436

To a mixture of methyl4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylate(Example 435) (126 mg), THF (2 mL) and methanol (2 mL), 10% aqueoussodium hydroxide (1 mL) was added and heated under reflux for 2 hours.To the reaction liquid, 10% hydrochloric acid was added to give a pH ofabout 7, and the resulting solid was collected by filtration. This solidwas purified by silica gel column chromatography (eluent;chloroform:methanol) to give4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylicacid (Example 436) (47 mg), which was a low-polarity product, as a lightyellow white powder and4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylicacid (Example 437) (59 mg), which was a high-polarity product, as alight yellow powder.

Example 438

To a mixture of4-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)amino]cyclohexanecarboxylicacid (Example 436) (62 mg), o-anisidine (42 mg) and DMF (2 mL),1-hydroxy-1H-benzotriazole monohydrate (46 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (65 mg) wereadded and stirred at room temperature for 7 hours. The reaction liquidwas poured into saturated aqueous sodium hydrogen carbonate andextracted with ethyl acetate. The organic layer was washed with waterand saturated aqueous sodium chloride sequentially and then dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified by silica gel columnchromatography (eluent; chloroform:methanol) to give6-ethyl-5-({4-[(2-methoxy-phenyl)carbamoyl]cyclohexyl}amino)-3-{[4-(4-methylpiperazin-1-yl)-3-(trifluoromethyl)phenyl]amino}pyrazine-2-carboxamide(33 mg) as a yellow powder.

Example 495

A mixture of6-chloro-3-{[3-(1,4-dioxa-8-azaspiro[4.5]deca-8-yl)-4-methoxyphenyl]amino}-5-[(trans-4-hydroxycyclohexyl)amino]pyrazine-2-carboxamide(Example 482) (0.80 g), acetic acid (4 mL) and water (4 mL) was stirredat 80° C. for 3 hours. To the reaction liquid, concentrated hydrochloricacid (1 mL) was added and stirred at 80° C. for 2 hours. The reactionliquid was cooled and concentrated under reduced pressure, and thenchloroform was added, followed by washing with saturated aqueous sodiumhydrogen carbonate. After the organic layer was dried over anhydrousmagnesium sulfate, the solvent was distilled off, followed bypurification by silica gel column chromatography (eluent;chloroform:methanol=10:1 to 30:1) to give6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide(0.74 g) as a yellow amorphous.

Example 499

To a mixture of6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-methoxy-3-(4-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide(Example 495) (0.346 mg), N-methylpiperazine (0.12 mL) and1,2-dichloroethane (10 mL), sodium triacetoxyborohydride (225 mg) wasadded and stirred at room temperature for 5 hours. After addition ofsaturated aqueous sodium hydrogen carbonate, the reaction liquid wasextracted with chloroform, and the organic layer was washed withsaturated aqueous sodium chloride. After drying over anhydrous sodiumsulfate, the solvent was distilled off under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent;chloroform:methanol:saturated aqueous ammonia=100:0:0 to 20:1:0.1) togive a crude product. The crude product was solidified with ethylacetate-diisopropyl ether and then washed with ethyl acetate to give6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-methoxy-3-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide(39 mg) as a light yellow solid.

Example 508

A mixture of6-bromo-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(Example 181) (50 mg), cyclopropylboronic acid (18 mg),tetrakistriphenylphosphine palladium (24 mg), potassium carbonate (71mg), dioxane (2.5 mL) and water (0.5 mL) was stirred at 115° C.overnight. After cooling, the reaction liquid was partitioned usingchloroform, saturated aqueous sodium hydrogen carbonate and saturatedaqueous sodium chloride. After drying, the organic layer wasconcentrated, and the resulting residue was purified by silica gelcolumn chromatography (eluent; chloroform:methanol:saturated aqueousammonia=100:0:0 to 10:1:0.1). The resulting residue was solidified withethyl acetate-hexane to give6-cyclopropyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide(10 mg) as a yellow solid.

Example 534

To a mixture of5-[(1-benzylpiperidin-4-yl)amino]-6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide(Example 507) (1.31 g), ethanol (26 mL) and acetic acid (13 mL),palladium hydroxide (0.65 g) was added and stirred under a hydrogenatmosphere at room temperature for 3 days. After the catalyst wasseparated by filtration, the solvent was concentrated and partitionedusing chloroform and saturated aqueous sodium hydrogen carbonate. Theorganic layer was concentrated to give6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(piperidin-4-ylamino)pyrazine-2-carboxamide(0.73 g) as a light yellow solid.

Tables 85 to 164 show the chemical structures of the compounds preparedin the above examples, and the chemical structures of the examplescompounds prepared by the same manner as shown in the above examplesusing corresponding starting materials. Tables 165 to 183 show thepreparation processes and physical and chemical data of these examplescompounds.

TABLE 7 Rex Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

TABLE 8 Rex Structure 15

16

17

18

19

20

21

22

23

24

25

26

27

28

TABLE 9 Rex Structure 29

30

31

32

33

34

35

36

37

38

39

40

41

42

TABLE 10 Rex Structure 43

44

45

46

47

48

49

50

51

52

53

54

55

56

TABLE 11 Rex Structure 57

58

59

60

61

62

63

64

65

66

67

68

69

70

TABLE 12 Rex Structure 71

72

73

74

75

76

77

78

79

80

81

82

83

84

TABLE 13 Rex Structure 85

86

87

88

89

90

91

92

93

94

95

96

97

98

TABLE 14 Rex Structure  99

100

101

102

103

104

105

106

107

108

109

110

111

112

TABLE 15 Rex Structure 113

114

115

116

117

118

119

120

121

122

123

124

125

126

TABLE 16 Rex Structure 127

128

129

130

131

132

133

134

135

136

137

138

139

140

TABLE 17 Rex Structure 141

142

143

144

145

146

147

148

149

150

151

152

153

154

TABLE 18 Rex Structure 155

156

157

158

159

160

161

162

163

164

165

166

167

168

TABLE 19 Rex Structure 169

170

171

172

173

174

175

176

177

178

179

180

181

182

TABLE 20 Rex Structure 183

184

185

186

187

188

189

190

191

192

193

194

195

196

TABLE 21 Rex Structure 197

198

199

200

201

202

203

204

205

206

207

208

209

210

TABLE 22 Rex Structure 211

212

213

214

215

216

217

218

219

220

221

222

223

224

TABLE 23 Rex Structure 225

226

227

228

229

230

231

232

233

234

235

236

237

238

TABLE 24 Rex Structure 239

240

241

242

243

244

245

246*¹

247*²

248*¹

249*²

250*³

251*⁴

252*³

TABLE 25 Rex Structure 253*³

254

255

256

257

258

259

260

261

262

263

264

265

266

TABLE 26 Rex Structure 267

268

269

270

271

272

273

274

275

276

277

278

279

280

TABLE 27 Rex Structure 281

282

283

284

285

286

287

288

289

290

291

292

293

294

TABLE 28 Rex Structure 295

296

297

298

299

300

301

302

303

304

305

306

307

308

TABLE 29 Rex Structure 309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

TABLE 30 Rex Structure 325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

TABLE 31 Rex Structure 341

342

343

344

345

346

347

348

349

350

351

352

353

354

TABLE 32 Rex Structure 355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

TABLE 33 Rex Structure 371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

TABLE 34 Rex Structure 387

388

389

390

391

392

393

394

395

396

397

398

399

400

401

402

TABLE 35 Rex Structure 403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

TABLE 36 Rex Structure 419

420

421

422

423

424

425

426

427

428

429

430

431

432

TABLE 37 Rex Structure 433

434

435

436

437

438

439

440

441

442

443

444

445

446

TABLE 38 Rex Structure 447

448

449

450

451

452

453

454

455

456

457

458

459

460

TABLE 39 Rex Structure 461

462

463

464

465

466

467

468

469

470

471

472

473

474

TABLE 40 Rex Structure 475

476

477

478

479

480

481

482

483

484

485

486

487

488

TABLE 41 Rex Structure 489

490

491

492

493

494

495

496

497

498

499

500

501

502

TABLE 42 Rex Structure 503

504

505

506

507

508

509

510

511

512

513

514

TABLE 43 Rex Structure 515

516

517

518

519

520

521

522

523

524

525

526

TABLE 44 Rex Structure 527

528

529

530

531

532

533

534

535

536

TABLE 45 Rex Structure 537

538

539

540

541

542

543

544

545

546

TABLE 46 Rex Structure 547

548

549

550

551

552

553

554

555

556

TABLE 47 Rex Structure 557

558

559

560

561

562

TABLE 48 Rex Syn Data 1 Rex299 ESI-: 402 2 Rex298 ESI-: 420 3 Rex292¹H-NMR (CDCl3): 1.11 (3H, br-s), 1.21 (3H, br-s), 2.17 (3H, s), 3.28(2H, br-s), 3.51 (2H, br-s), 3.66 (2H, br-s), 6.66-6.68 (2H, m), 7.03(1H, dd, J = 0.8 Hz, 8.0 Hz). 4 Rex4 EI: 236 5 Rex299 ESI-: 388 6 Rex298ESI-: 406 7 Rex292 ¹H-NMR (CDCl3): 1.50-1.65 (6H, m), 2.16 (3H, s), 3.36(2H, br-s), 3.71 (4H, m), 6.66-6.69 (2H, m), 7.02 (1H, d, J = 7.6 Hz). 8Rex4 EI: 248 9 Rex299 ¹H-NMR (DMSO-d6): 1.48-1.59 (6H, m), 2.30 (3H, s),2.41 (3H, s), 3.33 (2H, br-s), 3.54 (2H, br-s), 7.02 (1H, dd, J = 1.2Hz, 8.0 Hz), 7.28 (1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 4.0 Hz), 7.99(1H, d, J = 1.2 Hz), 9.16 (1H, d, J = 4.4 Hz), 12.68 (1H, s), 12.84 (1H,s). 10 Rex298 ESI-: 418 11 Rex292 ¹H-NMR (CDCl3): 1.24 (6H, d, J = 6.8Hz), 2.19 (3H, s), 3.70 (2H, br-s), 4.23-4.29 (1H, m), 5.85 (1H, br-s),6.97 (1H, dd, J = 1.6 Hz, 7.6 Hz), 7.06 (1H, d, J = 7.6 Hz), 7.13 (1H,d, J = 1.6 Hz). 12 Rex4 ¹H-NMR (CDCl3): 1.29 (6H, d, J = 6.4 Hz), 2.65(3H, s), 4.25-4.34 (1H, m), 5.99 (1H, br-s), 7.42 (1H, d, J = 8.0 Hz),7.94 (1H, dd, d = 2.0 Hz, 8.0 Hz), 8.30 (1H, d, J = 1.6 Hz).

TABLE 49 Rex Syn Data 13 Rex299 ¹H-NMR (DMSO-d6): 1.14 (6H, d, J = 6.4Hz), 2.31 (3H, s), 2.43 (3H, s), 4.06-4.11 (1H, m), 7.31 (1H, d, J = 8.0Hz), 7.47 (1H, d, J = 4.4 Hz), 7.54 (1H, dd, J = 1.6 Hz, 8.0 Hz), 8.14(1H, d, J = 7.6 Hz), 8.47 (1H, d, J = 1.6 Hz), 9.17 (1H, d, J = 4.4 Hz),12.69 (1H, s), 12.84 (1H, s). 14 Rex298 ESI-: 392 15 Rex299 ¹H-NMR(DMSO-d6): 2.31 (3H, s), 2.44 (3H, s), 2.76 (3H, d, J = 4.4 Hz), 7.31(1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 4.4 Hz), 7.52 (1H, dd, J = 1.6 Hz,8.0 Hz), 8.36 (1H, d, J = 4.8 Hz), 8.49 (1H, d, J = 1.6 Hz), 9.19 (1H,d, J = 4.4 Hz), 12.70 (1H, s), 12.85 (1H, s). 16 Rex298 ESI-: 364 17Rex299 ESI-: 424 18 Rex298 ESI-: 442 19 Rex299 ESI-: 436 20 Rex298 ESI-:454 21 Rex292 ¹H-NMR (CDCl3): 3.00 (3H, d, J = 4.9 Hz), 3.94 (2H, m),6.44 (1H, m), 6.58 (1H, dd, J = 2.4 Hz, 8.5 Hz), 6.64 (1H, d, J = 2.4Hz), 7.67 (1H, d, J = 8.5 Hz). 22 Rex4 ¹H-NMR (CDCl3): 3.07 (3H, d, J =4.9 Hz), 6.15 (1H, m), 7.82 (1H, d, J = 8.3 Hz), 8.17 (1H, dd, J = 2.2Hz, 8.3 Hz), 8.29 (1H, d, J = 2.2 Hz). 23 Rex299 ESI-: 366 24 Rex298ESI-: 384 25 Rex292 ¹H-NMR (CDCl3): 1.05 (3H, t, J = 7.1 Hz), 1.24 (3H,t, J = 7.1 Hz), 3.18 (2H, q, J = 7.1 Hz), 3.35 (1H, m), 3.83 (3H, m),6.56 (1H, dd, J = 2.2 Hz, 8.1 Hz), 6.67 (1H, d, J = 2.2 Hz), 7.03 (1H,d, J = 8.1 Hz).

TABLE 50 Rex Syn Data 26 Rex4 ¹H-NMR (CDCl3): 1.09(3H, t, J = 7.1 Hz),1.29 (3H, t, J = 7.1 Hz), 3.06-3.21 (2H, m), 3.35-3.44 (1H, m),3.76-3.85 (1H, m), 7.74 (1H, d, J = 8.3 Hz), 8.18 (1H, dd, J = 2.2 Hz,8.3 Hz), 8.29 (1H, d, J = 2.2 Hz). 27 Rex299 ESI-: 408 28 Rex298 ESI-:426 29 Rex292 ¹H-NMR (CDCl3): 1.08 (6H, d, J = 6.4 Hz), 2.21 (1H, s),3.40-3.47 (1H, m), 4.21 (1H, d, J = 6.8 Hz), 7.14-7.18 (1H, m). 30Rex299 ¹H-NMR (DMSO-d₆): 0.86-0.96 (6H, m), 2.43 (1H, s), 3.15-3.20 (1H,m), 3.35 (3H, s), 7.43-7.70 (4H, m), 8.23 (1H, s), 9.18 (1H, s), 12.79(1H, s), 13.06 (1H, s). 31 Rex298 ESI-: 428 32 Rex299 ¹H-NMR (DMSO-d6):2.32-2.54 (9H, m), 7.33- 7.70 (4H, m), 8.52 (1H, s), 9.18 (1H, s), 12.81(1H, s), 13.09 (1H, s). 33 Rex298 ESI-: 400 34 Rex299 ¹H-NMR (DMSO-d6):1.45-1.59 (6H, m), 2.54 (3H, s), 3.12 (2H, m), 3.56-3.63 (2H, m),7.28-7.30 (1H, m), 7.38-7.41 (1H, m), 7.58-7.59 (1H, m), 7.99-7.99 (1H,m), 9.16-9.17 (1H, m), 12.85 (1H, br-s), 13.13 (1H, br-s). 35 Rex298ESI-: 438 36 Rex292 ¹H-NMR (CDCl3): 1.25 (6H, d, J = 6.6 Hz), 3.94 (2H,m), 4.20-4.32 (1H, m), 6.22 (1H, m), 6.55- 6.58 (1H, m), 6.63 (1H, d, J= 2.2 Hz), 7.61 (1H, dd, J = 1.2 Hz, 8.3 Hz).

TABLE 51 Rex Syn Data 37 Rex4 ¹H-NMR (CDCl3): 1.30 (6H, d, J = 6.6 Hz),4.28- 4.36 (1H, m), 5.90 (1H, m), 7.78 (1H, d, J = 8.5 Hz), 8.16 (1H,dd, J = 2.2 Hz, 8.3 Hz), 8.28 (1H, d, J = 2.2 Hz). 38 Rex299 ¹H-NMR(DMSO-d6): 1.14 (6H, d, J = 6.6 Hz), 2.56 (3H, s), 4.01-4.02 (1H, m),7.36-7.37 (2H, m), 7.58-7.59 (1H, m), 7.94-7.95 (1H, m), 8.24-8.26 (1H,m), 9.17 (1H, m), 12.85 (1H, br-s), 13.14 (1H, br-s). 39 Rex298 ESI-:412 40 Rex292 ¹H-NMR (CDCl3): 1.43-1.50 (2H, m), 1.57-1.63 (4H, m),3.11-3.13 (4H, m), 3.84 (1H, s), 6.16- 6.25 (2H, m), 7.62-7.66 (1H, m).41 Rex41 ¹H-NMR (CDCl3): 1.54-1.63 (6H, m), 3.25 (4H, t, J = 5.6 Hz),4.04 (1H, s), 7.83 (1H, d, J = 0.2 Hz), 7.88 (1H, dd, J = 0.2 Hz, 8.8Hz), 8.07 (1H, d, J = 8.8 Hz). 42 Rex299 ESI-: 452 43 Rex298 ¹H-NMR(DMSO-d6): 1.44-1.50 (6H, m), 3.30- 3.04 (4H, m), 3.10 (1H, s), 3.85(1H, s), 7.46-7.48 (1H, m), 7.55-7.56 (1H, m), 7.64-7.66 (1H, m), 7.93(1H, br-s), 9.53 (1H, br-s). 44 Rex292 ¹H-NMR (CDCl3): 1.09 (6H, t, J =7.2 Hz), 2.28 (4H, q, J = 7.2 Hz), 3.84 (1H, s), 6.17-6.23 (2H, m),7.67-7.71 (1H, m). 45 Rex41 ¹H-NMR (CDCl3): 1.13 (6H, t, J = 7.2 Hz),3.37 (4H, q, J = 7.2 Hz), 4.04 (3H, s), 7.82 (1H, d, J = 2.8 Hz), 7.87(1H, dd, J = 2.8 Hz, 8.8 Hz), 8.12 (1H, d, J = 8.8 Hz). 46 Rex299 ESI-:440 47 Rex298 ESI-: 458

TABLE 52 Rex Syn Data 48 Rex48 ¹H-NMR (CDCl3): 1.26 (6H, d, J = 6.4 Hz),3.66 (2H, br-s), 4.25-4.31 (1H, m), 6.57 (1H, br-s), 6.69-6.73 (1H, m),6.89 (1H, dd, J = 8.4 Hz, 11.6 Hz), 7.35 (1H, dd, J = 3.2 Hz, 6.8 Hz).49 Rex299 ¹H-NMR (DMSO-d6): 1.14 (6H, d, J = 6.4 Hz), 2.39 (3H, s),4.01-4.06 (1H, m), 7.24 (1H, t, J = 9.2 Hz), 7.49-7.53 (2H, m), 7.88(1H, dd, J = 2.8 Hz, 6.4 Hz), 8.18 (1H, d, J = 8.0 Hz), 9.16 (1H, d, J =4.4 Hz), 12.74 (1H, s), 12.96 (1H, s). 50 Rex298 ¹H-NMR (DMSO-d6): 1.14(6H, d, J = 6.8 Hz), 2.41 (3H, s), 4.01-4.07 (1H, m), 7.24 (1H, t, J =9.2 Hz), 7.62-7.66 (1H, m), 7.82-7.84 (1H, m), 7.87 (1H, s), 8.14 (1H,s), 8.15 (1H, m), 9.38 (1H, s). 51 Rex48 ¹H-NMR (CDCl3): 1.50-1.65 (6H,m), 3.28 (2H, br- s), 3.63 (2H, br-s), 3.71 (2H, br-s), 6.61-6.65 (2H,m), 6.86 (1H, t, J = 7.6 Hz). 52 Rex299 ¹H-NMR (DMSO-d6): 1.44-1.61 (6H,m), 2.45 (3H, s), 3.21 (2H, br-s), 3.59 (2H, br-s), 7.26 (1H, t, J = 8.8Hz), 7.49-7.53 (2H, m), 7.63 (1H, dd, J = 2.4 Hz, 6.4 Hz), 9.14 (1H, d,J = 4.4 Hz), 12.72 (1H, s), 12.89 (1H, s). 53 Rex298 ¹H-NMR (DMSO-d6):1.45-1.62 (6H, m), 2.33 (3H, s), 3.22 (2H, m), 3.59 (2H, br-s), 7.26(1H, t, J = 8.8 Hz), 7.57-7.62 (2H, m), 7.86 (1H, s), 8.13 (1H, s), 9.35(1H, s). 54 Rex299 ¹H-NMR (DMSO-d6): 2.45 (3H, s), 3.26 (2H, br-s), 3.53(2H, t, J = 4.8 Hz), 3.63 (4H, br-s), 7.28 (1H, t, J = 8.8 Hz),7.51-7.57 (2H, m), 7.65 (1H, dd, J = 2.8 Hz, 6.0 Hz), 9.14 (1H, d, J =4.4 Hz), 12.73 (1H, s), 12.89 (1H, s).

TABLE 53 Rex Syn Data 55 Rex298 ¹H-NMR (DMSO-d6): 2.41 (3H, s), 3.27(2H, m), 3.54 (2H, t, J = 4.8 Hz), 3.64 (4H, br-s), 7.28 (1H, t, J = 8.8Hz), 7.61-7.64 (2H, m), 7.88 (1H, br-s), 8.14 (1H, br-s), 9.38 (1H, s).56 Rex292 ¹H-NMR (CDC3): 1.08 (3H, t, J = 7.2 Hz), 1.23 (3H, t, J = 7.2Hz), 3.24 (2H, q, J = 7.2 Hz), 3.55 (2H, m), 3.70 (2H, br-s), 6.56 (1H,dd, J = 3.2 Hz, 5.6 Hz), 6.62 (1H, m), 6.85 (1H, t, J = 8.8 Hz). 57Rex299 ¹H-NMR (DMSO-d6): 1.01 (3H, t, J = 7.2 Hz), 1.13 (3H, t, J = 7.2Hz), 2.45 (3H, s), 3.17 (2H, q, J = 7.2 Hz), 3.44 (2H, m), 7.26 (1H, t,J = 8.8 Hz), 7.46 (1H, m), 7.52 (1H, d, J = 4.4 Hz), 7.67 (1H, dd, J =2.8 Hz, 6.0 Hz), 9.15 (1H, d, J = 4.4 Hz), 12.73 (1H, s), 12.94 (1H, s).58 Rex298 ¹H-NMR (DMSO-d6): 1.02 (3H, t, J = 7.2 Hz), 1.13 (3H, t, J =7.2 Hz), 2.40 (3H, s), 3.18 (2H, q, J = 7.2 Hz), 3.45 (2H, q, J = 7.2Hz), 7.27 (1H, t, J = 9.2 Hz), 7.58-7.61 (2H, m), 7.87 (1H, br-s), 8.14(1H, br-s), 9.35 (1H, s). 59 Rex292 ¹H-NMR (CDCl3): 1.05 (6H, d, J = 6.4Hz), 3.27- 3.49 (1H, m), 3.90 (1H, s), 4.55 (1H, d, J = 6.4 Hz),6.62-6.28 (2H, m), 7.65-7.69 (1H, m). 60 Rex41 ¹H-NMR (CDCl3): 1.08 (6H,t, J = 6.8 Hz), 3.48 (1H, q, J = 7.6 Hz), 4.11 (1H, s), 4.75 (1H, d, J =7.6 Hz), 7.88 (1H, d, J = 2.0 Hz), 7.94 (1H, dd, J = 2.0 Hz, 8.4 Hz),8.12 (1H, d, J = 8.4 Hz). 61 Rex299 ¹H-NMR (DMSO-d6): 0.94-0.99 (6H, m),3.18- 3.24 (1H, m), 2.49 (1H, s), 3.92 (1H, s), 7.06-7.08 (1H, m),7.20-7.23 (1H, m), 7.39-7.40 (1H, m), 7.61-7.69 (2H, m), 9.20 (1H,br-s), 12.88 (1H, br- s), 13.28 (1H, br-s).

TABLE 54 Rex Syn Data 62 Rex298 ESI-: 444 63 Rex292 ¹H-NMR (CDCl3):1.40-1.46 (2H, m), 1.62-1.67 (4H, m), 2.96-2.99 (4H, m), 3.97 (1H,br-s), 7.06- 7.10 (2H, m), 7.15-7.18 (1H, m). 64 Rex41 ¹H-NMR (CDCl3):1.45-1.71 (7H, m), 3.06 (4H, t, J = 5.6 Hz), 7.46-7.52 (1H, m),8.00-8.04 (1H, m), 8.43-8.46 (1H, m). 65 Rex299 ESI-: 440 66 Rex298¹H-NMR (DMSO-d6): 1.31-1.38 (4H, m), 1.51- 1.55 (7H, m), 2.44 (1H, s),2.83-2.92 (7H, m), 7.56-7.58 (2H, m), 8.14-8.26 (3H, m), 9.77 (1H,br-s). 67 Rex292 ¹H-NMR (CDCl3): 1.43-1.45 (2H, m), 1.64 (4H, m), 2.22(1H, s), 3.21 (2H, m), 3.66-3.76 (4H, m), 6.48-6.51 (2H, m), 6.94 (1H,d, J = 8.0 Hz). 68 Rex4 ¹H-NMR (CDCl3): 1.43-1.87 (6H, m), 2.42 (3H, s),3.13-3.15 (2H, m), 3.69-3.83 (2H, m), 7.32 (1H, d, J = 8.4 Hz),8.07-8.11 (2H, m). 69 Rex299 ESI-: 400 70 Rex298 ESI-: 418 71 Rex292¹H-NMR (CD3OD): 2.23 (3H, s), 2.84 (3H, s), 6.50-6.55 (2H, m), 7.14 (1H,d, J = 8.4 Hz). 72 Rex4 ¹H-NMR (CDCl3): 2.54 (3H, s), 3.04 (3H, d, J =4.8 Hz), 5.80 (1H, br-s), 7.49 (1H, d, J = 8.4 Hz), 8.04-8.12 (1H, m).73 Rex299 ESI-: 346 74 Rex298 ESI-: 364 75 Rex292 ¹H-NMR (CDCl3):1.54-1.62 (6H, m), 3.20-3.23 (2H, m), 3.62-3.64 (1H, m), 3.77 (5H, m),6.20 (1H, d, J = 2.0 Hz), 6.27 (1H, dd, J = 2.0 Hz, 8.1 Hz), 7.02 (1H,d, J = 8.1 Hz). 76 Rex299 ESI-: 416

TABLE 55 Rex Syn Data 77 Rex298 ESI−: 434 78 Rex292 ¹H-NMR (CDCl3):1.45-1.47 (2H, m), 1.65 (4H, m), 2.17 (3H, s), 3.18-3.21 (2H, m),3.59-3.66 (3H, m), 3.78-3.82 (1H, m), 6.49 (1H, d, J = 2.7 Hz), 6.60(1H, dd, J = 2.7 Hz, 8.3 Hz), 6.97 (1H, d, J = 8.3 Hz). 79 Rex4 ¹H-NMR(CDCl3): 1.48-1.54 (2H, m), 1.70 (4H, m), 2.42 (3H, s), 3.16-3.20 (2H,m), 3.73-3.80 (2H, m), 7.39 (1H, d, J = 8.5 Hz), 8.05 (1H, d, J = 2.2Hz), 8.12 (1H, dd, J = 2.2 Hz, 8.5 Hz). 80 Rex299 ESI−: 400 81 Rex298ESI−: 418 82 Rex292 ¹H-NMR (CDCl3): 2.31 (3H, s), 2.98 (3H, d, J = 4.9Hz), 3.60 (2H, m), 5.69 (1H, m), 6.64 (1H, dd, J = 2.7 Hz, 8.1 Hz), 6.70(1H, d, J = 2.7 Hz), 6.98 (1H, d, J = 8.1 Hz). 83 Rex299 ESI−: 346 84Rex298 ESI−: 364 85 Rex48 ¹H-NMR (CDCl3): 2.97 (3H, d, J = 4.8 Hz), 4.03(2H, br-s), 5.76 (1H, br-s), 6.77 (1H, dd, J = 2.4 Hz, 8.0 Hz), 6.90(1H, d, J = 2.4 Hz), 7.33 (1H, d, J = 8.0 Hz). 86 Rex299 ¹H-NMR(DMSO-d6): 2.51 (3H, s), 2.73 (3H, d, J = 4.4 Hz), 7.48 (1H, d, J = 8.4Hz), 7.63-7.65 (2H, m), 8.22 (1H, d, J = 1.6 Hz), 8.38 (1H, d, J = 4.8Hz), 9.18 (1H, d, J = 4.4 Hz), 12.89 (1H, s), 13.27 (1H, s). 87 Rex298¹H-NMR (DMSO-d6): 2.45 (3H, s), 2.73 (3H, d, J = 4.8 Hz), 7.48 (1H, d, J= 8.4 Hz), 7.88 (1H, d, J = 8.8 Hz), 7.89 (1H, s), 8.12 (1H, d, J = 2.0Hz), 8.17 (1H, s), 8.38 (1H, m), 9.62 (1H, s).

TABLE 56 Rex Syn Data 88 Rex48 ¹H-NMR (CDCl3): 3.01 (3H, dd, J = 1.2 Hz,5.2 Hz), 3.69 (2H, br-s), 6.70-6.74 (1H, m), 6.77 (1H, br-s), 6.90 (1H,dd, J = 8.4 Hz, 11.6 Hz), 7.38 (1H, dd, J = 3.2 Hz, 6.4 Hz). 89 Rex299¹H-NMR (DMSO-d6): 2.49 (3H, s), 2.77 (3H, d, J = 4.4 Hz), 7.26 (1H, t, J= 8.8 Hz), 7.53-7.58 (2H, m), 7.95 (1H, dd, J = 2.8 Hz, 6.4 Hz), 8.24(1H, br- s), 9.16 (1H, d, J = 4.4 Hz), 12.75 (1H, s), 12.96 (1H, s). 90Rex298 ¹H-NMR (DMSO-d6): 2.40 (3H, s), 2.77 (3H, d, J = 4.8 Hz), 7.26(1H, t, J = 10.0 Hz), 7.64-7.68 (1H, m), 7.87 (1H, br-s), 7.92 (1H, dd,J = 2.4 Hz, 6.4 Hz), 8.14 (1H, br-s), 8.21 (1H, br-s), 9.39 (1H, br-s).91 Rex292 ¹H-NMR (CDCl3): 2.55 (3H, s), 3.91 (3H, s), 6.22-6.30 (2H, m),7.65-7.69 (1H, m). 92 Rex41 ¹H-NMR (CDCl3): 2.66 (3H, d, J = 5.2 Hz),4.11 (3H, s), 4.84 (1H, d, J = 5.2 Hz), 7.89 (1H, d, J = 2.0 Hz), 7.94(1H, dd, J = 2.0 Hz, 8.8 Hz), 8.12 (1H, d, J = 8.8 Hz). 93 Rex299 ESI−:398 94 Rex298 ESI−: 416 95 Rex292 ¹H-NMR (CDCl3): 2.97 (3H, d, J = 4.6Hz), 3.90 (3H, s), 3.96 (2H, m), 6.20 (1H, d, J = 2.2 Hz), 6.34 (1H, dd,J = 2.2 Hz, 8.5 Hz), 7.66 (1H, m), 8.04 (1H, d, J = 8.5 Hz). 96 Rex4¹H-NMR (CDCl3): 3.04 (3H, d, J = 4.9 Hz), 4.09 (3H, s), 7.74 (1H, m),7.84 (1H, d, J = 2.2 Hz), 7.93 (1H, dd, J = 2.2 Hz, 8.5 Hz), 8.39 (1H,d, J = 8.5 Hz). 97 Rex299 ESI−: 362

TABLE 57 Rex Syn Data 98 Rex298 ESI−: 380 99 Rex48 ¹H-NMR (CDCl3):0.83-0.88 (1H, m), 1.42-1.65 (5H, m), 3.15 (2H, dd, J = 9.2 Hz, 15.2Hz), 3.64-3.76 (2H, m), 4.01 (2H, br-s), 6.78 (1H, dd, J = 2.4 Hz, 8.4Hz), 6.90 (1H, d, J = 2.8 Hz), 7.05 (1H, d, J = 8.4 Hz). 100 Rex299¹H-NMR (DMSO-d6): 1.37-1.59 (6H, m), 2.54 (3H, s), 3.06-3.11 (2H, m),3.51-3.62 (2H, m), 7.40 (1H, d, J = 8.4 Hz), 7.61-7.66 (2H, m), 8.27(1H, d, J = 2.0 Hz), 9.18 (1H, d, J = 4.0 Hz), 12.89 (1H, s), 13.28 (1H,s). 101 Rex298 ¹H-NMR (DMSO-d6): 1.37-1.59 (6H, m), 2.45 (3H, s),3.06-3.11 (2H, m), 3.52-3.62 (2H, m), 7.40 (1H, d, J = 8.0 Hz), 7.90(1H, br-s), 7.92 (1H, m), 8.16 (1H, br-s), 8.19 (1H, d, J = 2.0 Hz),9.62 (1H, s). 102 Rex353 ESI−: 346 103 Rex353 ESI−: 454 104 Rex353 ESI−:346 105 Rex353 ESI−: 346 106 Rex299 ¹H-NMR (DMSO-d6): 2.53 (3H, s), 2.72(3H, d, J = 4.4 Hz), 7.41 (1H, d, J = 8.8 Hz), 7.48-7.56 (2H, m), 8.36(1H, d, J = 4.6 Hz), 9.16 (1H, d, J = 3.7 Hz), 12.80 (1H, s), 13.10 (1H,s). 107 Rex298 ¹H-NMR (DMSO-d6): 2.43 (3H, s), 2.73 (3H, d, J = 4.6 Hz),7.41 (1H, d, J = 8.5 Hz), 7.65 (1H, dd, J = 2.7 Hz, 8.8 Hz), 7.77 (1H,d, J = 2.4 Hz), 7.88 (1H, s), 8.14 (1H, s), 8.35 (1H, d, J = 4.6 Hz),9.43 (1H, s).

TABLE 58 Rex Syn Data 108 Rex353 ¹H-NMR (CDCl3): 1.29 (3H, t, J = 7.6Hz), 2.87 (2H, q, J = 7.3 Hz), 3.04 (3H, s), 5.56 (1H, br-s), 6.25 (1H,br-s), 7.34 (1H, d, J = 8.8 Hz), 7.74 (1H, br-s), 7.81 (1H, dd, J = 2.9Hz, 8.8 Hz), 7.93 (1H, d, J = 2.7 Hz), 10.95 (1H, br-s). 109 Rex353¹H-NMR (CDCl3): 1.31 (3H, t, J = 7.6 Hz), 2.89 (2H, q, J = 7.3 Hz), 3.03(3H, d, J = 4.9 Hz), 4.04 (3H, s), 5.53 (1H, br-s), 6.12 (1H, br-s),7.28 (1H, m), 7.49 (1H, s), 7.74 (1H, br-s), 8.58 (1H, d, J = 8.3 Hz),11.43 (1H, br-s). 110 Rex292 ¹H-NMR (CDCl3): 2.18 (3H, s), 2.98 (3H, d,J = 4.9 Hz), 3.88 (2H, m), 5.97 (1H, m), 6.64 (1H, d, J = 8.1 Hz), 7.44(1H, dd, J = 2.0 Hz, 8.3 Hz), 7.51 (1H, m). 111 Rex4 ¹H-NMR (CDCl3):2.64 (3H, s), 3.05 (3H, d, J = 4.9 Hz), 6.17 (1H, m), 7.67 (1H, dd, J =2.0 Hz, 8.3 Hz), 7.76 (1H, d, J = 2.0 Hz), 8.00 (1H, d, J = 8.3 Hz). 112Rex353 ESI−: 346 113 Rex353 ESI−: 400 114 Rex292 ¹H-NMR (CDCl3): 2.21(3H, s), 2.99 (3H, d, J = 4.9 Hz), 3.70 (2H, m), 5.72 (1H, m), 6.71-6.77(2H, m), 7.00-7.04 (1H, m). 115 Rex353 ¹H-NMR (CDCl3): 1.30 (3H, t, J =7.3 Hz), 2.42 (3H, s), 2.87 (2H, q, J = 7.3 Hz), 3.02 (3H, d, J = 4.9Hz), 5.50 (1H, m), 5.75 (1H, m), 7.09-7.11 (1H, m), 7.75 (1H, m),8.16-8.18 (1H, m), 10.74 (1H, m). 116 Rex353 ESI−: 366 117 Rex353 ESI−:325

TABLE 59 Rex Syn Data 118 Rex292 ¹H-NMR (CDCl3): 2.98 (3H, d, J = 4.9Hz), 3.85 (2H, br-s), 6.06 (1H, br-s), 6.98-7.01 (2H, m), 7.25-7.29 (1H,m). 119 Rex353 ¹H-NMR (CDCl3): 1.31 (3H, t, J = 7.6 Hz), 2.92 (2H, q, J= 7.3 Hz), 3.05 (3H, d, J = 4.9 Hz), 5.57 (1H, br-s), 6.13 (1H, br-s),7.18 (1H, m), 7.52 (1H, m), 7.73 (1H, s), 8.87 (1H, d, J = 8.5 Hz),11.15 (1H, br-s). 120 Rex292 ¹H-NMR (CDCl3): 3.00 (3H, d, J = 4.9 Hz),4.19 (2H, br-s), 5.92 (1H, br-s), 6.80 (1H, dd, J = 1.7 Hz, 7.6 Hz),6.87 (1H, dd, J = 1.7 Hz, 7.6 Hz), 7.08 (1H, d, J = 7.6 Hz). 121 Rex4¹H-NMR (CDCl3): 3.06 (3H, s), 5.57 (1H, br-s), 6.04 (1H, br-s), 7.42(1H, d, J = 8.1 Hz), 7.74 (1H, dd, J = 1.5 Hz, 7.6 Hz), 7.83 (1H, dd, J= 2.0 Hz, 8.1 Hz). 122 Rex353 ¹H-NMR (CDCl3): 1.31 (3H, t, J = 7.6 Hz),2.91 (2H, q, J = 7.3 Hz), 3.04 (3H, d, J = 4.9 Hz), 5.56 (1H, br-s),5.95 (1H, br-s), 7.21 (1H, m), 7.34 (1H, m), 7.74 (1H, br-s), 8.56 (1H,m), 11.40 (1H, br-s). 123 Rex299 ¹H-NMR (DMSO-d6): 2.84 (3H, s), 7.21(2H, t, J = 9.6 Hz), 7.52 (1H, t, J = 9.6 Hz), 7.53 (2H, s), 7.64 (1H,d, J = 4.0 Hz), 8.22 (2H, d, J = 9.2 Hz), 9.24 (1H, d, J = 4.0 Hz),12.92 (1H, br-s), 13.73 (1H, s). 124 Rex298 ESI−: 343 125 Rex353 ESI−:325 126 Rex353 ESI−: 398 127 Rex353 ESI+: 334

TABLE 60 Rex Syn Data 128 Rex353 ¹H-NMR (DMSO-d6): 1.24 (3H, t, J = 7.6Hz), 2.89 (2H, q, J = 7.3 Hz), 4.53 (2H, s), 6.92 (1H, d, J = 8.5 Hz),7.11-7.16 (2H, m), 8.02 (1H, br-s), 8.25 (1H, br-s), 10.78 (1H, br-s),11.06 (1H, br-s). 129 Rex353 ESI−: 265 130 Rex353 ESI−: 350 131 Rex353ESI−: 289 132 Rex353 ESI+: 488 133 Rex353 ¹H-NMR (CDCl3): 1.31 (3H, t, J= 7.2 Hz), 2.64 (6H, s), 2.91 (2H, q, J = 7.2 Hz), 4.30 (1H, br-s), 5.60(1H, br-s), 7.56 (1H, br-s), 7.77 (1H, m), 7.95 (1H, d, J = 8.0 Hz),11.12 (1H, br-s). 134 Rex353 ¹H-NMR (CDCl3): 1.30 (3H, t, J = 7.2 Hz),2.89 (2H, q, J = 7.6 Hz), 2.99 (3H, s), 5.59 (1H, br-s), 6.60 (1H,br-s), 7.53 (1H, dd, J = 2.4 Hz, 9.2 Hz), 7.60 (1H, d, J = 8.8 Hz), 7.75(1H, br-s), 7 96 (1H, d, J = 2.4 Hz), 10.95 (1H, s). 135 Rex353 ESI+:368 136 Rex353 ESI+: 364 137 Rex292 ¹H-NMR (CDCl3): 2.44 (3H, s), 2.50(3H, s), 6.79 (1H, dd, J = 2.4 Hz, 8.4 Hz), 7.06 (1H, d, J = 8.4 Hz),7.25 (1H, d, J = 2.4 Hz). 138 Rex353 ESI−: 382 139 Rex292 ¹H-NMR(CDCl3): 3.15-3.17 (4H, m), 3.70-3.72 (4H, m), 3.85 (3H, s), 4.13 (2H,br-s), 6.19 (1H, d, J = 2.0 Hz), 6.23 (1H, dd, J = 2.0 Hz, 8.4 Hz), 7.01(1H, d, J = 8.4 Hz). 140 Rex41 ¹H-NMR (CDCl3): 3.28-3.30 (4H, m),3.72-3.74 (4H, m), 4.06 (3H, s), 7.86 (1H, d, J = 2.0 Hz), 7.89 (1H, dd,J = 2.0 Hz, 8.4 Hz), 8.80 (1H, d, J = 8.4 Hz,).

TABLE 61 Rex Syn Data 141 Rex353 ESI−: 454 142 Rex353 ¹H-NMR (DMSO-d6):1.24 (3H, t, J = 7.6 Hz), 2.79 (2H, q, J = 7.3 Hz), 4.56 (2H, s), 6.84(1H, d, J = 8.5 Hz), 6.98 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.46 (1H, d, J =2.2 Hz), 8.01 (1H, br-s), 8.24 (1H, br-s), 10.65 (1H, br-s), 11.11 (1H,br-s). 143 Rex353 ESI+: 317 144 Rex353 ¹H-NMR (DMSO-d6): 1.24 (3H, t, J= 7.6 Hz), 2.78 (2H, q, J = 7.3 Hz), 4.20-4.24 (4H, m), 6.81-6.89 (2H,m), 7.29 (1H, d, J = 2.4 Hz), 7.98 (1H, br-s), 8.21 (1H, br-s), 10.98(1H, br-s). 145 Rex48 ¹H-NMR (CDCl3): 3.36 (3H, s), 3.53 (2H, t, J = 5.1Hz), 3.61 (2H, m), 4.01 (2H, br-s), 6.14 (1H, br-s), 6.76 (1H, dd, J =2.0 Hz, 8.3 Hz), 6.91 (1H, d, J = 2.2 Hz), 7.33 (1H, d, J = 8.3 Hz). 146Rex353 ¹H-NMR (CDCl3): 1.31 (3H, t, J = 7.6 Hz), 2.90 (2H, q, J = 7.3Hz), 3.39 (3H, s), 3.58 (2H, m), 3.64 (2H, m), 5.79 (1H, br-s), 6.38(1H, br-s), 7.52 (1H, d, J = 3.7 Hz), 7.75 (1H, br-s), 7.87 (1H, dd, J =2.0 Hz, 8.3 Hz), 11.05 (1H, br-s). 147 Rex353 ¹H-NMR (CDCl3): 1.24-1.59(9H, m), 2.90 (2H, q, J = 7.6 Hz), 3.10-3.17 (4H, m), 3.95 (3H, s), 5.59(1H, br-s), 7.13 (1H, d, J = 8.8 Hz), 7.63 (1H, d, J = 8.4 Hz),7.75-7.81 (3H, m), 11.16 (1H, br-s). 148 Rex353 ¹H-NMR (CDCl3): 1.25(3H, t, J = 7.6 Hz), 2.60 (3H, s), 2.92 (2H, q, J = 7.6 Hz), 5.59 (1H,br-s), 7.28 (1H, m), 7.73 (1H, br-s), 7.75 (1H, m), 8.44 (1H, d, J = 2.0Hz), 10.99 (1H, br-s). 149 Rex353 ¹H-NMR (CDCl3): 1.21-1.34 (3H, m),2.82-2.92 (5H, m), 5.61 (1H, br-s), 7.51 (1H, d, J = 6.8 Hz), 7.72-7.75(1H, m), 7.87 (1H, d, J = 6.8 Hz), 8.42 (1H, d, J = 2.8 Hz), 10.99 (1H,br-s).

TABLE 62 Rex Syn Data 150 Rex353 ESI+: 364 151 Rex353 ¹H-NMR (CDCl3):1.25 (3H, t, J = 7.6 Hz), 2.92 (3H, q, J = 7.6 Hz), 5.63 (1H, br-s),7.53 (1H, dd, J = 3.6 Hz, 6.9 Hz), 7.76 (1H, br-s), 7.90 (1H, d, J = 6.0Hz), 8.78 (1H, d, J = 3.6 Hz), 11.27 (1H, br-s). 152 Rex353 ESI+: 329153 Rex353 ¹H-NMR (CDCl3): 1.34 (3H, t, J = 7.6 Hz), 2.95 (2H, q, J =7.6 Hz), 5.65 (1H, br-s), 7.74 (1H, dd, J = 2.0 Hz, 9.2 Hz), 7.79 (1H,br-s), 8.02 (1H, d, J = 9.2 Hz), 9.28 (1H, d, J = 2.0 Hz), 11.25 (1H,br-s). 154 Rex353 ¹H-NMR (CDCl3): 1.30 (3H, t, J = 7.6 Hz), 2.86 (2H, q,J = 7.6 Hz), 3.79 (3H, s), 5.49 (1H, m), 6.44 (1H, d, J = 3.2 Hz), 7.01(1H, d, J = 3.2 Hz), 7.15 (1H, dd, J = 0.2 Hz, 8.4 Hz), 7.54 (1H, d, J =8.4 Hz), 7.74 (1H, m), 7.98 (1H, s), 10.84 (1H, m). 155 Rex292 ¹H-NMR(CDC3): 2.84 (3H, s), 3.37 (2H, br-s), 3.99 (1H, br-s), 6.62 (1H, d, J =8.4 Hz), 6.82 (1H, dd, J = 2.8 Hz, 8.4 Hz), 6.86 (1H, d, J = 2.8 Hz).156 Rex353 ¹H-NMR (CDCl3): 1.28 (3H, t, J = 7.6 Hz), 2.85 (2H, q, J =7.6 Hz), 2.91 (3H, d, J = 4.8 Hz), 4.32 (1H, br-s), 5.51 (1H, br-s),6.73 (1H, d, J = 8.4 Hz), 7.66-7.70 (3H, m), 10.50 (1H, br-s). 157Rex292 ¹H-NMR (DMSO-d6): 1.67-1.78 (2H, m), 2.07 (2H, m), 3.03-3.27 (8H,m), 3.73 (3H, s), 3.90-4.16 (3H, m), 5.79 (2H, br-s), 6.29 (1H, d, J =8.5 Hz), 6.50-6.54 (2H, m). 158 Rex503 ESI+: 338 159 Rex353 ESI+: 491160 Rex160 ¹H-NMR (CDCl3): 1.35 (3H, t, J = 7.6 Hz), 3.02 (2H, q, J =7.6 Hz). 161 Rex353 ESI+: 375

TABLE 63 Rex Syn Data 162 Rex292 ESI+: 276 163 Rex444 ESI+: 306 164Rex353 ESI+: 459 165 Rex353 ESI+: 376 166 Rex353 ¹H-NMR (CDCl3): 1.28(3H, t, J = 7.6 Hz), 2.84 (2H, q, J = 7.6 Hz), 3.46-3.48 (4H, m),3.83-3.85 (4H, m), 5.55 (1H, br-s), 6.67 (1H, d, J = 8.8 Hz), 8.43 (1H,d, J = 2.4 Hz), 10.45 (1H, br-s). 167 Rex292 ESI+: 276 168 Rex444 ESI+:306 169 Rex353 ESI+: 459 170 Rex353 ESI+: 552 171 Rex353 ¹H-NMR (CDCl3):1.28 (3H, t, J = 7.2 Hz), 2.84 (2H, q, J = 7.2 Hz), 3.12-3.14 (4H, m),3.86-3.88 (4H, m), 5.51 (1H, br-s), 6.91 (1H, dd, J = 2.4 Hz, 7.2 Hz),7.55 (1H, dd, J = 2.4 Hz, 7.2 Hz), 7.71 (1H, br-s), 10.58 (1H, br-s).172 Rex353 ¹H-NMR (CDCl3): 1.28 (3H, t, J = 7.6 Hz), 2.31 (3H, s), 2.36(3H, s), 2.84 (2H, q, J = 7.6 Hz), 2.92-2.94 (4H, m), 5.48 (1H, br-s),7.02 (1H, d, J = 8.8 Hz), 7.34 (1H, d, J = 2.4 Hz), 7.55 (1H, dd, J =2.7 Hz, 8.5 Hz), 7.71 (1H, br-s), 10.60 (1H, br-s). 173 Rex353 ¹H-NMR(CDCl3): 1.28 (3H, t, J = 7.6 Hz), 1.68-1.74 (6H, m), 1.92-1.95 (2H, m),2.29-2.36 (7H, m), 2.50-2.65 (8H, m), 2.84 (2H, q, J = 7.6 Hz),3.13-3.16 (2H, m), 5.54 (1H, br-s), 6.98 (1H, d, J = 6.5 Hz), 7.33 (1H,d, J = 2.6 Hz), 7.51 (1H, d, J = 2.7 Hz), 7.71 (1H, br-s), 10.58 (1H,br-s).

TABLE 64 Rex Syn Data 174 Rex353 ¹H-NMR (CDCl3): 1.29 (3H, t, J = 7.3Hz), 2.37 (3H, s), 2.62 (4H, m), 2.85 (2H, q, J = 7.3 Hz), 3.03 (4H, m),5.53 (1H, br-s), 7.05 (1H, d, J = 8.8 Hz), 7.51 (1H, dd, J = 2.7 Hz, 8.8Hz), 7.72 (1H, d, J = 2.4 Hz), 10.70 (1H, br-s). 175 Rex353 ¹H- NMR(CDCl3): 1.28 (t, J = 7.2 Hz, 3H), 1.49 (s, 9H), 2.84 (q, J = 7.2 Hz,2H), 3.09 (m, 4H), 3.58 (m, 4H), 5.62 (br-s, 1H), 6.92 (d, J = 9.2 Hz,2H), 7.54 (d, J = 9.2 Hz, 2H), 7.71 (br-s, 1H), 10.60 (s, 1H). 176Rex292 ¹H-NMR (CDCl3): 1.60 (2H, br-s), 2.04-2.17 (4H, m), 2.91-2.94(4H, m), 6.80 (1H, dd, J = 2.8 Hz, 8.4 Hz), 6.91 (1H, d, J = 2.8 Hz),7.17 (1H, d, J = 8.4 Hz). 177 Rex516 ¹H-NMR (CDCl3): 2.13-2.22 (4H, m),3.18-3.20 (4H, m), 7.36 (1H, d, J = 8.8 Hz), 8.35 (1H, dd, J = 2.4 Hz,9.2 Hz), 8.53 (1H, d, J = 2.4 Hz). 178 Rex353 ESI−: 462 179 Rex353 ESI+:400 180 Rex292 ¹H-NMR (CDCl3): 0.16-0.20 (2H, m), 0.55-0.59 (2H, m),0.97 (1H, m), 2.40 (2H, d, J = 6.4 Hz), 2.75 (2H, m), 2.96 (4H, m), 3.72(2H, m), 6.79 (1H, dd, J = 2.8 Hz, 8.4 Hz), 6.89 (1H, d, J = 2.8 Hz),7.24 (1H, d, J = 8.4 Hz). 181 Rex516 EI: 329 182 Rex353 ESI+: 483 183Rex292 ¹H-NMR (CDCl3): 1.80-1.88 (1H, m), 2.06-2.14 (1H, m), 2.24 (6H,s), 2.85-3.20 (5H, m), 3.65 (2H, br-s), 6.78 (1H, dd, J = 2.9 Hz, 8.5Hz), 6.90 (1H, d, J = 2.7 Hz), 7.14 (1H, d, J = 8.5 Hz).

TABLE 65 Rex Syn Data 184 Rex516 ¹H-NMR (CDCl3): 1.90-1.97 (1H, m),2.21-2.29 (1H, m), 2.32 (3H, s), 2.77-2.82 (1H, m), 3.43-3.53 (1H, m),3.62-3.67 (3H, m), 6.79 (1H, d, J = 9.5 Hz), 8.16 (1H, dd, J = 2.7 Hz,9.5 Hz), 8.53 (1H, d, J = 2.7 Hz). 185 Rex353 ¹H-NMR (CDCl3): 1.29 (3H,t, J = 7.3 Hz), 1.84-1.89 (1H, m), 2.12-2.16 (1H, m), 2.26 (6H, s),2.83-2.89 (3H, m), 3.20-3.41 (4H, m), 5.57 (1H, br-s), 7.09 (1H, d, J =8.8 Hz), 7.71-7.82 (3H, m), 10.68 (1H, br-s). 186 Rex353 ¹H-NMR (CDCl3):1.10-1.15 (3H, m), 1.30 (3H, t, J = 7.3 Hz), 2.45-2.52 (2H, m),2.85-2.97 (10H, m), 5.57 (1H, br-s), 7.37-7.39 (1H, m), 7.73 (1H, br-s),7.87-7.88 (2H, m), 10.86 (1H, br-s). 187 Rex292 ¹H-NMR (CDCl3): 1.04(6H, d, J = 6.3 Hz), 2.28-2.33 (2H, m), 2.81 (2H, dd, J = 2.0 Hz, 9.0Hz), 3.02-3.07 (2H, m), 3.69 (2H, br-s), 6.78 (1H, dd, J = 2.7 Hz, 8.5Hz), 6.89 (1H, d, J = 2.9 Hz), 7.15 (1H, d, J = 8.5 Hz). 188 Rex516¹H-NMR (CDCl3): 1.10 (3H, s), 1.11 (3H, s), 2.48-2.53 (2H, m), 3.08-3.13(2H, m), 3.22 (2H, d, J = 10.7 Hz), 7.22 (1H, d, J = 9.0 Hz), 8.29 (1H,dd, J = 2.7 Hz, 9.0 Hz), 8.50 (1H, d, J = 2.7 Hz). 189 Rex353 ¹H-NMR(CDCl3): 1.05-1.09 (6H, m), 1.22-1.46 (3H, m), 2.34-2.40 (2H, m),2.71-3.76 (6H, m), 5.57 (1H, br-s), 7.32 (1H, d, J = 8.5 Hz), 7.74 (1H,br-s), 7.85-7.88 (2H, m), 10.85 (1H, br-s).

TABLE 66 Rex Syn Data 190 Rex292 ¹H-NMR (CDCl3): 1.41 (3H, s), 1.42 (3H,s), 2.68 (3H, s), 2.87-2.90 (2H, m), 2.81 (2H, dd, J = 2.0 Hz, 9.0 Hz,2H), 3.00 (m, 2H), 3.23 (m, 2H), 3.81 (br-s), 6.80 (1H, dd, J = 2.9 Hz,8.5 Hz), 6.88 (1H, d, J = 2.9 Hz), 7.24 (1H, d, J = 7.8 Hz). 191 Rex516¹H-NMR (CDCl3): 1.15 (3H, s), 1.16 (3H, s), 2.36 (3H, s), 2.46-2.50 (2H,m), 2.79-2.85 (2H, m), 3.19 (2H, dd, J = 2.7 Hz, 9.0 Hz), 7.22-7.24 (1H,m), 8.30 (1H, dd, J = 2.7 Hz, 9.0 Hz), 8.50 (1H, d, J = 2.7 Hz). 192Rex353 ¹H-NMR (CDCl3): 1.11 (6H, m), 1.30 (3H, t, J = 7.3 Hz), 2.33-2.44(5H, m), 2.67-2.79 (2H, m), 2.85-2.91 (4H, m), 5.54 (1H, br-s), 7.33(1H, d, J = 8.3 Hz), 7.73 (1H, br-s), 7.85-7.87 (2H, m), 10.85 (1H,br-s). 193 Rex353 ESI+: 362 194 Rex194 ESI+: 377 195 Rex353 ESI+: 389196 Rex353 ESI+: 403 197 Rex353 ¹H-NMR (CDCl3): 1.30 (3H, t, J = 7.6Hz), 1.48 (9H, s), 2.76-2.91 (6H, m), 3.55 (4H, m), 5.57 (1H, br-s),7.31 (1H, d, J = 8.8 Hz), 7.74 (1H, br-s), 7.86-7.90 (2H, m), 10.89 (1H,br-s). 198 Rex353 ¹H-NMR (CDCl3): 1.28 (3H, t, J = 7.6 Hz), 1.48 (9H,s), 2.32 (3H, s), 2.82-2.88 (6H, m), 3.56 (4H, t, J = 4.9 Hz), 5.52 (1H,br-s), 6.98 (1H, d, J = 8.5 Hz), 7.36 (1H, d, J = 2.7 Hz), 7.55 (1H, dd,J = 2.7 Hz, 8.5 Hz), 7.72 (1H, br-s), 10.62 (1H, br-s).

TABLE 67 Rex Syn Data 199 Rex516 1H- NMR (CDCl3): 0.99 (s, 6H), 1.29 (t,J = 5.6 Hz, 2H), 1.59-1.67 (m, 2H), 2.46 (s, 2H), 2.67 (m, 2H), 3.67(br- s, 2H), 6.77 (dd, J = 2.9 Hz, 8.5 Hz, 1H), 6.89 (d, J = 2.7 Hz,1H), 7.16 (d, J = 6.5 Hz, 1H). 200 Rex194 ESI+: 417 201 Rex194 ESI+: 476202 Rex292 ¹H-NMR (CDCl3): 1.81-1.85 (2H, m), 1.99-2.03 (2H, m),2.18-2.21 (4H, m), 2.79-2.84 (2H, m), 3.01-3.04 (2H, m), 3.12-3.34 (4H,m), 3.66-3.69 (2H, m), 9.92 (1H, dd, J = 2.4 Hz, 8.0 Hz), 6.98 (1H, d, J= 2.4 Hz), 7.24 (1H, d, J = 8.0 Hz). 203 Rex516 EI: 343 204 Rex353 ESI+:497 205 Rex353 ESI−: 437 206 Rex353 ESI−: 472 207 Rex292 ¹H-NMR (CDCl3):0.81 (3H, d, J = 6.4 Hz), 1.48 (3H, d, J = 6.6 Hz), 2.68 (2H, q, J =11.0 Hz), 2.81 (2H, d, J = 4.9 Hz), 2.93 (1H, dd, J = 2.9 Hz, 12.9 Hz),3.17 (1H, br-s), 3.29-3.44 (2H, m), 3.87 (2H, br-s), 6.83 (1H, dd, J =2.7 Hz, 8.5 Hz), 6.89 (1H, d, J = 2.7 Hz), 7.29 (1H, d, J = 8.3 Hz). 208Rex516 ¹H-NMR (CDCl3): 0.79 (3H, d, J = 6.3 Hz), 1.04 (3H, d, J = 6.4Hz), 2.16-2.21 (2H, m), 2.28-2.34 (4H, m), 2.44-2.50 (1H, m), 2.86-2.90(2H, m), 7.56 (1H, d, J = 8.8 Hz), 8.40 (1H, dd, J = 2.7 Hz, 8.8 Hz),8.55 (1H, d, J = 2.7 Hz). 209 Rex353 ESI+: 471 210 Rex292 EI: 219 211Rex516 EI: 249 212 Rex353 ESI+: 403

TABLE 68 Rex Syn Data 213 Rex292 ¹H-NMR (CDCl3): 1.52-1.55 (2H, m), 2.01(2H, dt, J = 4.4 Hz, 8.4 Hz), 2.12-2.16 (2H, m), 2.84-2.94 (6H, m), 6.87(1H, dd, J = 2.4 Hz, 8.4 Hz), 6.94 (1H, d, J = 2.4 Hz), 7.10-7.21 (4H,m), 7.29 (1H, d, J = 8.4 Hz). 214 Rex516 ¹H-NMR (CDCl3): 1.52-1.55 (2H,m), 2.01 (2H, dt, J = 4.4 Hz, 12.8 Hz), 2.12-2.16 (2H, m), 2.84-3.31(6H, m), 6.86-6.89 (1H, m), 6.95 (1H, m), 7.10-7.19 (4H, m), 7.30 (1H,d, J = 8.4 Hz). 215 Rex353 ESI−: 528 216 Rex353 ESI+: 403 217 Rex292 EI:344 218 Rex516 EI: 374 219 Rex353 ESI−: 526 220 Rex292 ¹H-NMR (CDCl3):2.34 (3H, s), 2.51 (4H, t, J = 4.8 Hz), 3.17 (4H, t, J = 4.8 Hz), 3.63(2H, br-s), 6.58 (2H, s). 221 Rex516 ¹H-NMR (CDCl3): 2.38 (3H, s), 2.58(4H, m), 3.36 (4H, t, J = 4.8 Hz), 8.15 (2H, s). 222 Rex353 ESI−: 441223 Rex292 ¹H-NMR (CDCl3): 1.41-1.53 (10H, m), 1.69 (2H, t, J = 7.1 Hz),2.86 (2H, s), 3.10 (2H, t, J = 6.8 Hz), 3.59 (2H, br-s), 6.77 (1H, d, J= 2.7 Hz, 8.5 Hz), 6.90 (1H, dd, J = 2.5 Hz, 9.5 Hz), 7.08 (1H, d, J =8.8 Hz). 224 Rex516 ¹H-NMR (CDCl3): 1.42-1.57 (10H, m), 1.85 (2H, t, J =7.1 Hz), 3.33 (2H, s), 3.61 (2H, t, J = 7.0 Hz), 6.77 (1H, d, J = 9.5Hz), 8.14 (1H, dd, J = 2.7 Hz, 9.5 Hz), 8.53 (1H, d, J = 2.9 Hz).

TABLE 69 Rex Syn Data 225 Rex353 ¹H-NMR (CDCl3): 1.28 (3H, t, J = 7.6Hz), 1.43-1.55 (10H, m), 2.32 (3H, s), 1.75 (2H, t, J = 7.1 Hz), 2.85(2H, q, J = 7.6 Hz), 3.06 (2H, s), 3.32 (2H, t, J = 6.8 Hz), 5.50 (1H,br-s), 7.02 (1H, d, J = 9.0 Hz), 7.69-7.71 (2H, m), 7.80 (1H, d, J = 2.7Hz), 10.61 (1H, br-s). 226 Rex353 ¹H-NMR (CDCl3): 1.29 (3H, t, J = 7.6Hz), 1.49 (9H, s), 2.85 (2H, q, J = 7.6 Hz), 2.98 (4H, m), 3.61 (4H, t,J = 5.1 Hz), 3.90 (3H, s), 5.52 (1H, br- s), 6.87 (1H, d, J = 8.5 Hz),7.14 (1H, dd, J = 2.4 Hz, 8.5 Hz), 7.38 (1H, d, J = 2.2 Hz), 7.73 (1H,br-s), 10.70 (1H, br-s). 227 Rex353 ESI+: 370 228 Rex413 ESI−: 343 229Rex412 ¹H-NMR (CDCl3): 1.50 (9H, s), 2.37 (2H, m), 3.63-3.65 (2H, m),4.06 (2H, m), 5.66 (1H, m), 7.44 (1H, d, J = 8.3 Hz), 8.35 (1H, dd, J =2.2 Hz, 8.3 Hz), 8.54 (1H, d, J = 2.2 Hz). 230 Rex353 ¹H-NMR (CDCl3):1.30 (3H, t, J = 7.3 Hz), 1.49 (9H, s), 1.60-1.78 (2H, m), 2.81 (2H, m),2.88 (2H, q, J = 7.3 Hz), 3.00-3.06 (1H, m), 4.24 (1H, m), 5.56 (1H, m),7.37 (1H, d, J = 8.5 Hz), 7.74 (1H, m), 7.85 (1H, dd, J = 2.4 Hz, 8.5Hz), 7.92 (1H, d, J = 2.4 Hz), 10.90 (1H, br-s). 231 Rex353 ESI+: 403232 Rex353 ESI+: 392 233 Rex353 ESI+: 390 234 Rex292 ¹H-NMR (CDCl3):2.18 (3H, s), 2.38 (3H, s), 2.58 (4H, br-s), 2.83 (4H, br-s), 3.63 (2H,br-s), 6.35 (1H, dd, J = 2.8 Hz, 8.4 Hz), 6.98 (1H, d, J = 8.4 Hz), 7.81(1H, d, J = 2.8 Hz), 8.66 (1H, br-s).

TABLE 70 Rex Syn Data 235 Rex353 ESI+: 432 236 Rex292 ¹H-NMR (CDCl3 +CD3OD): 2.42 (3H, s), 2.69 (4H, br-s), 2.86 (4H, br-s), 3.05 (3H, s),6.44 (1H, dd, J = 2.8 Hz, 8.4 Hz), 6.87 (1H, d, J = 2.8 Hz), 7.08 (1H,d, J = 8.8 Hz). 237 Rex516 ¹H-NMR (CDCl3): 2.39 (3H, s), 2.64 (4H,br-s), 2.97 (4H, t, J = 4.8 Hz), 3.19 (3H, s), 7.28 (1H, d, J = 8.8 Hz),7.53 (1H, br-s), 7.97 (1H, dd, J = 2.4 Hz, 8.4 Hz), 8.31 (1H, d, J = 2.4Hz). 238 Rex353 ESI+: 468 239 Rex292 ¹H-NMR (CDCl3): 2.35 (3H, s), 2.45(4H, br-s), 2.85 (4H, t, J = 4.8 Hz), 3.54 (2H, br-s), 6.62-6.65 (2H,m), 6.92 (1H, d, J = 9.2 Hz), 7.29 (1H, t, J = 7.6 Hz), 7.36 (2H, t, J =7.6 Hz), 7.57 (2H, d, J = 7.2 Hz). 240 Rex240 ¹H-NMR (CDCl3): 2.27 (3H,s), 2.34 (4H, br-s), 2.99 (4H, t, J = 4.8 Hz), 7.01 (1H, d, J = 9.2 Hz),7.35 (1H, t, J = 7.2 Hz), 7.44 (2H, t, J = 7.2 Hz), 7.58 (2H, d, J = 7.2Hz), 8.08 (1H, d, J = 2.8 Hz), 8.14 (1H, dd, J = 2.8 Hz, 9.2 Hz). 241Rex516 ESI+: 348 242 Rex353 ESI+: 451 243 Rex292 ¹H-NMR (CDCl3): 1.91(3H, s), 2.34 (3H, s), 2.55 (4H, br-s), 2.87 (4H, m), 3.22 (3H, s), 3.64(2H, br-s), 6.47 (1H, s), 6.66 (1H, d, J = 8.8 Hz), 6.95 (1H, d, J = 8.4Hz). 244 Rex244 ¹H-NMR (CDCl3): 1.98 (3H, s), 2.35 (3H, s), 2.56 (4H, t,J = 4.8 Hz), 3.18 (4H, dd, J = 3.6 Hz, 5.6 Hz), 3.26 (3H, s), 7.05 (1H,d, J = 9.2 Hz), 7.98 (1H, d, J = 2.4 Hz), 8.14 (1H, dd, J = 2.4 Hz, 8.8Hz).

TABLE 71 Rex Syn Data 245 Rex353 ESI+: 446 246 Rex246 ¹H-NMR (CDCl3):0.90 (3H, t, J = 7.8 Hz), 1.40-1.55 (15H, m), 1.61-1.64 (2H, m),1.78-1.82 (2H, m), 3.39 (1H, m), 4.42 (1H, m). 247 Rex247 ¹H-NMR(CD3OD): 0.90 (3H, t, J = 7.6 Hz), 1.30-1.54 (6H, m), 1.62-1.65 (3H, m),2.52-2.58 (1H, m). 248 Rex246 ¹H-NMR (CDCl3): 0.91 (3H, t, J = 7.6 Hz),1.32-1.49 (13H, m), 1.54 (2H, q, J = 7.6 Hz), 1.60-1.66 (2H, m),1.88-1.93 (2H, m), 3.59 (1H, m), 4.55 (1H, m). 249 Rex249 ¹H-NMR(CD3OD): 0.89 (3H, t, J = 7.6 Hz), 1.20-1.31 (2H, m), 1.38-1.45 (2H, m),1.55 (2H, q, J = 7.6 Hz), 1.68-1.81 (4H, m), 2.70-2.75 (1H, m). 250Rex250 ¹H-NMR (CDCl3): 0.91 (6H, d, J = 6.8 Hz), 1.43-1.49 (11H, m),1.51-1.63 (5H, m), 1.81-1.83 (2H, m), 3.37 (1H, m), 4.41 (1H, m). 251Rex251 ¹H-NMR (DMSO-d6): 0.82 (6H, d, J = 6.8 Hz), 1.24-1.31 (2H, m),1.43-1.53 (3H, m), 1.65-1.67 (4H, m), 2.85-2.89 (1H, m), 3.87 (1H, m),7.88 (2H, m). 252 Rex250 ¹H-NMR (CDCl3): 0.92 (6H, d, J = 6.8 Hz),1.43-1.45 (11H, m), 1.52-1.55 (2H, m), 1.64-1.76 (3H, m), 1.88-1.92 (2H,m), 3.68 (1H, m), 4.53 (1H, m). 253 Rex253 ¹H-NMR (DMSO-d6): 0.83 (6H,d, J = 6.8 Hz), 1.25-1.32 (2H, m), 1.48 (2H, m), 1.62-1.68 (3H, m),1.82-1.88 (2H, m), 3.17 (1H, m), 3.92 (1H, m), 7.84 (2H, m). 254 Rex353ESI+: 453

TABLE 72 Rex Syn Data 255 Rex292 ¹H-NMR (CDCl3): 1.48 (9H, s), 1.85-1.93(2H, m), 2.23 (3H, s), 2.93-3.02 (4H, m), 3.45-3.59 (6H, m), 6.47 (1H,d, J = 8.3 Hz), 6.53 (1H, s), 6.86 (1H, d, J = 8.3 Hz). 256 Rex353¹H-NMR (CDCl3): 1.28 (3H, t, J = 7.3 Hz), 1.49 (9H, s), 1.91-1.96 (2H,m), 2.31 (3H, s), 2.84 (2H, q, J = 7.3 Hz), 3.00-3.08 (4H, m), 3.56-3.61(4H, m), 5.50 (1H, br-s), 7.01-7.04 (1H, m), 7.34 (1H, s), 7.52 (1H, m),7.71 (1H, br-s), 10.60 (1H, br-s). 257 Rex292 ¹H-NMR (CD3OD): 1.49 (9H,s), 2.02-2.20 (6H, m), 2.37 (3H, s), 2.77-2.86 (2H, m), 3.27-3.34 (6H,m), 3.48-3.65 (6H, m), 3.96 (1H, t, J = 15.4 Hz), 7.18-7.23 (3H, m). 258Rex503 ¹H-NMR (CDCl3): 1.47 (9H, s), 1.69-1.90 (6H, m), 2.35 (3H, s),2.61-2.80 (7H, m), 3.30-3.33 (2H, m), 3.42-3.50 (4H, m), 6.96 (1H, d, J= 8.3 Hz), 8.00-8.03 (2H, m). 259 Rex516 ESI+: 235 260 Rex292 ¹H-NMR(CDCl3): 1.63 (2H, m), 2.03-2.94 (21H, m), 3.63 (2H, br-s), 6.34 (1H, d,J = 8.4 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.81 (1H, s), 8.61 (1H, br-s).261 Rex503 ¹H-NMR (CDCl3): 1.64-1.73 (2H, m), 2.12 (2H, d, J = 12.8 Hz),2.24 (3H, s), 2.29-2.38 (1H, m), 2.31 (3H, s), 2.50 (4H, br-s), 2.66(4H, br-s), 2.75 (2H, t, J = 12.4 Hz), 3.15 (2H, d, J = 12.0 Hz), 7.16(1H, d, J = 8.8 Hz), 7.92 (1H, dd, J = 2.8 Hz, 8.8 Hz), 8.07 (1H, br-s),9.16 (1H, d, J = 2.4 Hz). 262 Rex516 ¹H-NMR (CDCl3): 2.29 (3H, s), 2.68(4H, t, J = 6.0 Hz), 3.27 (4H, t, J = 6.0 Hz), 7.23 (1H, d, J = 8.8 Hz),7.97 (1H, dd, J = 2.4 Hz, 8.8 Hz), 8.16 (1H, br-s), 9.22 (1H, br-s).

TABLE 73 Rex Syn Data 263 Rex353 ESI+: 515 264 Rex292 ¹H-NMR (CDCl3):1.63 (2H, m), 1.89 (3H, s), 1.97 (2H, m), 2.56-3.21 (19H, m), 3.61 (2H,br-s), 6.47 (1H, d, J = 2.8 Hz), 6.61 (1H, dd, J = 2.8 Hz, 8.4 Hz), 6.91(1H, d, J = 8.8 Hz). 265 Rex244 ¹H-NMR (CDCl3): 1.62 (2H, m), 1.96 (3H,s), 2.00 (2H, m), 2.29 (3H, s), 2.36 (1H, m), 2.48 (4H, br- s), 2.48(4H, br-s), 2.61 (4H, br-s), 2.86 (4H, m), 3.48 (3H, s), 3.51 (2H, t, J= 10.8 Hz), 7.03 (1H, d, J = 9.2 Hz), 7.96 (1H, d, J = 2.8 Hz), 8.11(1H, dd, J = 2.8 Hz, 9.2 Hz). 266 Rex353 ESI+: 529 267 Rex292 ¹H-NMR(CDCl3): 0.62-0.66 (2H, m), 0.91-0.96 (2H, m), 2.35 (1H, m), 2.35 (3H,s), 2.57 (4H, br-s), 2.96 (4H, s), 3.42 (2H, br-s), 6.08 (1H, d, J = 2.4Hz), 6.46 (1H, dd, J = 2.4 Hz, 8.4 Hz), 6.88 (1H, d, J = 8.4 Hz). 268Rex240 ¹H-NMR (CDCl3): 0.83 (2H, m), 1.09 (2H, m), 2.15 (1H, m), 2.38(3H, s), 2.62 (4H, br-s), 3.21 (4H, br-s), 6.99 (1H, d, J = 8.4 Hz),7.68 (1H, d, J = 2.8 Hz), 7.99 (1H, dd, J = 2.4 Hz, 8.8 Hz). 269 Rex353ESI+: 415 270 Rex292 EI: 251 271 Rex516 EI: 281 272 Rex353 ESI−: 433 273Rex353 ESI+: 482 274 Rex292 ¹H-NMR (CD3OD): 2.54 (3H, s), 2.57 (3H, s),2.90-2.94 (4H, m), 2.99-3.02 (4H, m), 6.80 (1H, dd, J = 2.4 Hz, 8.8 Hz),7.09 (1H, d, J = 8.8 Hz), 7.22 (1H, d, J = 2.4 Hz).

TABLE 74 Rex Syn Data 275 Rex516 ¹H-NMR (CDCl3): 2.39 (3H, s), 2.60 (4H,m), 3.04 (3H, d, J = 4.8 Hz), 3.12-3.15 (4H, m), 7.17 (1H, d, J = 8.8Hz), 8.23 (1H, dd, J = 2.4 Hz, 8.8 Hz), 8.80 (1H, d, J = 2.4 Hz). 276Rex353 ESI+: 432 277 Rex292 ¹H-NMR (CD3OD): 1.69-1.71 (2H, m), 1.92-1.95(2H, m), 2.35 (3H, s), 2.55 (3H, s), 2.57-2.82 (9H, m), 3.14 (2H, m),3.31 (2H, m), 3.34 (6H, s), 6.86-6.88 (1H, m), 7.20-7.22 (2H, m). 278Rex503 ¹H-NMR (CDCl3): 1.71-1.80 (2H, m), 1.96-1.99 (2H, m), 2.30 (3H,s), 2.49-2.64 (9H, m), 2.80 (6H, s), 2.84 (2H, m), 3.57-3.60 (2H, m),7.31 (1H, d, J = 9.2 Hz), 8.30 (1H, dd, J = 2.8 Hz, 9.2 Hz), 8.71 (1H,d, J = 2.8 Hz). 279 Rex516 ¹H-NMR (CDCl3): 2.69-2.72 (4H, m), 2.86 (6H,s), 3.47-3.50 (4H, m), 7.39 (1H, d, J = 8.8 Hz), 8.36 (1H, dd, J = 2.4Hz, 8.8 Hz), 8.71 (1H, d, J = 2.4 Hz). 280 Rex353 ESI+: 565 281 Rex292¹H-NMR (CDCl3): 2.48 (3H, s), 2.98 (4H, m), 3.31 (7H, m), 6.90 (1H, dd,J = 2.8 Hz, 8.4 Hz), 7.21 (1H, d, J = 2.8 Hz), 7.27 (1H, d, J = 8.4 Hz).282 Rex516 EI: 328 283 Rex353 ESI+: 468 284 Rex292 ¹H-NMR (CDCl3): 2.88(3H, s), 2.96 (3H, s), 3.14 (3H, s), 3.19-3.56 (8H, m), 7.09 (1H, s),7.29 (2H, m). 285 Rex516 ¹H-NMR (CDCl3): 2.34 (3H, s), 2.49-2.51 (4H,m), 2.88 (3H, s), 3.13-3.16 (2H, m), 3.15 (3H, s), 3.38 (2H, m), 6.64(1H, d, J = 8.8 Hz), 8.14-8.18 (2H, m).

TABLE 75 Rex Syn Data 286 Rex353 ESI+: 446 287 Rex287 EI: 211 288 Rex291ESI+: 244 289 Rex292 FAB+: 214 290 Rex287 EI: 211 291 Rex291 FAB+: 244292 Rex292 FAB+: 214 293 Rex298 ESI+: 401 294 Rex299 ESI+: 383 295Rex298 ESI+: 415 296 Rex298 ESI+: 415 297 Rex299 ESI+: 397 298 Rex298ESI−: 371 299 Rex299 ESI−: 353 300 Rex298 ESI−: 371 301 Rex299 ESI−: 354302 Rex299 ESI+: 397 303 Rex298 ESI+: 310 304 Rex304 ESI+: 306 305Rex298 ESI+: 352 306 Rex299 FAB+: 334 307 Rex298 ESI+: 338 308 Rex298ESI+: 330, 332 309 Rex298 ESI+: 366 310 Rex299 ESI+: 348 311 Rex311FAB+: 350 312 Rex299 ESI−: 318 313 Rex298 ESI+: 374 314 Rex299 ESI+: 356315 Rex298 ESI+: 387 316 Rex298 ESI+: 401

TABLE 76 Rex Syn Data 317 Rex339 ESI+: 292 318 Rex304 ESI+: 326, 328 319Rex339 ESI−: 310 320 Rex299 APCI−: 367 321 Rex299 ESI−: 381 322 Rex298APCI−: 400 323 Rex298 ESI−: 336 324 Rex298 ESI+: 364 325 Rex299 ESI+:384 326 Rex298 ESI+: 388 327 Rex299 APCI−: 368 328 Rex298 ESI+: 392 329Rex298 ESI+: 404 330 Rex298 ESI+: 326 331 Rex299 ESI−: 318 332 Rex298ESI+: 388 333 Rex298 ESI+: 427 334 Rex299 ESI−: 344 335 Rex299 ESI−: 386336 Rex299 ESI−: 373 337 Rex304 ESI+: 322 338 Rex299 ESI−: 407 339Rex339 ESI+: 308 340 Rex346 ESI+: 412 341 Rex349 ESI+: 370 342 Rex342ESI+: 387, 389 343 Rex342 FAB+: 369 344 Rex298 ESI+: 346 345 Rex298ESI+: 372 346 Rex346 ESI+: 370 347 Rex346 ESI+: 396

TABLE 77 Rex Syn Data 348 Rex349 ESI+: 354 349 Rex349 ESI+: 328 350Rex298 ESI+: 372 351 Rex298 ESI+: 407, 409 352 Rex298 ESI+: 330 353Rex353 ESI+: 355 354 Rex299 ESI+: 389, 391 355 Rex346 ESI+: 396 356Rex298 ESI+: 330 357 Rex346 ESI+: 354 358 Rex349 ESI+: 354 359 Rex298ESI+: 310, 312 360 Rex353 ESI+: 308, 310 361 Rex346 ESI+: 354 362 Rex349ESI+: 312 363 Rex349 ESI+: 312 364 Rex364 ESI+: 292 365 Rex298 ESI+: 364366 Rex346 ESI+: 388 367 Rex298 ESI+: 364 368 Rex346 ESI+: 388 369Rex349 ESI+: 346 370 Rex349 ESI+: 346 371 Rex298 ESI+: 372 372 Rex346ESI+: 396 373 Rex349 ESI+: 354 374 Rex298 ESI+: 296 375 Rex298 ESI+: 374376 Rex298 ESI+: 330 377 Rex298 ESI+: 330 378 Rex298 ESI+: 398

TABLE 78 Rex Syn Data 379 Rex353 FAB+: 327 380 Rex346 ESI+: 422 381Rex346 ESI−: 396 382 Rex346 ESI+: 320 383 Rex346 ESI+: 354 384 Rex346ESI+: 354 385 Rex349 ESI+: 380 386 Rex349 ESI+: 356 387 Rex349 ESI+: 278388 Rex349 ESI+: 312 389 Rex349 ESI+: 312 390 Rex353 ESI+: 278 391Rex353 ESI+: 369, 371 392 Rex353 ESI+: 361, 363 393 Rex353 ESI+: 323 394Rex353 ESI+: 323 395 Rex353 ESI+: 292 396 Rex397 ESI+: 355 397 Rex397ESI+: 355 398 Rex398 ESI+: 234, 236 399 Rex399 ESI+: 229 400 Rex400ESI+: 129 401 Rex353 ESI+: 328 402 Rex353 ESI−: 343 403 Rex353 ESI+: 317404 Rex353 ESI+: 333 405 Rex353 ESI+: 328 406 Rex516 ESI+: 335 407Rex292 ESI+: 305 408 Rex353 ESI+: 322 409 Rex353 ESI+: 368

TABLE 79 Rex Syn Data 410 Rex353 ESI+: 348 411 Rex353 ESI+: 361 412Rex412 FAB+: 335 413 Rex413 ESI+: 306 414 Rex353 ESI+: 375 415 Rex353ESI+: 405 416 Rex353 ESI+: 405 417 Rex417 ESI+: 387 418 Rex353 ESI+: 458419 Rex353 ESI+: 433 420 Rex353 ESI+: 375 421 Rex516 ESI+: 349 422Rex292 ESI+: 319 423 Rex353 ESI+: 488, 490 424 Rex353 ESI+: 443 425Rex353 ESI+: 460 426 Rex516 ESI+: 373 427 Rex353 ESI+: 405 428 Rex353ESI+: 362 429 Rex353 ESI+: 360 430 Rex430 EI: 256, 258 431 Rex430 EI:270, 272 432 Rex432 ESI+: 321 433 Rex432 ESI+: 335 434 Rex292 ESI+: 291435 Rex292 ESI+: 305 436 Rex292 ESI+: 343 437 Rex353 FAB+: 489 491 438Rex454 ESI−: 409 439 Rex353 ESI+: 405 440 Rex440 ESI+: 538

TABLE 80 Rex Syn Data 441 Rex455 ESI+: 311 442 Rex353 ESI+: 443 443Rex353 ESI+: 374 444 Rex444 ESI+: 252 445 Rex292 ESI+: 222 446 Rex353ESI+: 355, 357 447 Rex353 ESI+: 405 448 Rex464 ESI+: 408 449 Rex468ESI+: 274 450 Rex353 ESI+: 457 451 Rex516 ESI+: 305 452 Rex292 ESI+: 275453 Rex353 ESI+: 458 454 Rex454 ESI+: 441 455 Rex455 ESI+: 341 456Rex516 ESI+: 290 457 Rex292 ESI+: 260 458 Rex353 ESI+: 443 459 Rex516ESI+: 379 460 Rex292 ESI+: 349 461 Rex353 ESI+: 405 462 Rex454 ESI+: 441463 Rex455 APCI/ESI+: 341 464 Rex464 ESI+: 355 465 Rex464 ESI+: 438 466Rex467 ESI+: 277 467 Rex467 ESI+: 291 468 Rex468 ESI+: 221 469 Rex468ESI+: 304 470 Rex353 ESI+: 404, 406 471 Rex353 ESI+: 487, 489

TABLE 81 Rex Syn Data 472 Rex472 ESI+: 275 473 Rex473 APCI/ESI+: 279 474Rex292 APCI/ESI+: 249 475 Rex516 APCI/ESI+: 237 476 Rex353 APCI/ESI+:432, 434 477 Rex292 APCI/ESI+: 207 478 Rex454 FAB+: 411 479 Rex455 ESI+:311 480 Rex464 ESI+: 325 481 Rex468 ESI+: 191 482 Rex464 ESI+: 408 483Rex464 ESI+: 438 484 Rex468 ESI+: 274 485 Rex353 ESI+: 409 486 Rex468ESI+: 304 487 Rex353 ESI+: 404 488 Rex353 ESI+: 374 489 Rex353 ESI+: 487490 Rex353 ESI+: 457 491 Rex353 APCI/ESI+: 390, 392 492 Rex502 EI: 220493 Rex503 ESI+: 419 494 Rex455 ESI+: 319 495 Rex444 ESI+: 295 496Rex464 ESI+: 333 497 Rex292 ESI+: 265 498 Rex292 ESI+: 303 499 Rex444ESI+: 279 500 Rex353 APCI/ESI+: 486, 488 501 Rex353 ESI+: 420 502 Rex502APCI/ESI+: 251

TABLE 82 Rex Syn Data 503 Rex503 APCI/ESI+: 335 504 Rex292 APCI/ESI+:305 505 Rex353 APCI/ESI+: 406 506 Rex353 APCI/ESI+: 433 507 Rex353APCI/ESI+: 420 508 Rex353 APCI/ESI+: 419 509 Rex353 APCI/ESI+: 488 510Rex502 APCI/ESI+: 235 511 Rex503 APCI/ESI+: 319 512 Rex292 APCI/ESI+:239 513 Rex353 ESI+: 472 514 Rex432 ESI+: 308 515 Rex432 ESI+: 322 516Rex516 ESI+: 279 517 Rex292 ESI+: 249 518 Rex516 ESI+: 295 519 Rex292APCI/ESI+: 265 520 Rex353 ESI+: 404 521 Rex353 ESI+: 420 522 Rex292ESI+: 292 523 Rex292 ESI+: 278 524 Rex353 ESI+: 475, 477 525 Rex353ESI+: 488, 490 526 Rex353 ESI+: 502, 504 527 Rex353 ESI+: 474, 476 528Rex353 ESI+: 474 529 Rex353 ESI+: 461 530 Rex467 ESI+: 278 531 Rex353ESI+: 461, 463 532 Rex353 ESI+: 460, 462 533 Rex430 EI: 270, 272

TABLE 83 Rex Syn Data 534 Rex432 ESI+: 335 535 Rex292 ESI+: 305 536Rex353 ESI+: 488, 490 537 Rex432 ESI+: 322 538 Rex292 ESI+: 292 539Rex353 ESI+: 475, 477 540 Rex353 ESI+: 532, 534 541 Rex516 ESI+: 319 542Rex292 ESI+: 289 543 Rex545 ESI+: 389 544 Rex353 ESI+: 435 545 Rex545APCI/ESI+: 419 546 Rex417 ESI+: 470 547 Rex353 APCI/ESI+: 488 548 Rex3531H-NMR (CDCl3): 1.28 (3H, t, J = 7.3 Hz), 2.36 (3H, S), 2.62 (4H, br-s),2.85 (2H, q, J = 7.6 Hz), 3.10 (4H, br-s), 5.50 (1H, br-s), 6.91-6.99(1H, m), 7.25 (1H, br-s), 7.53 (1H, d, J = 14.4 Hz), 7.71 (1H, br- s),10.71 (1H, br-s) 549 Rex353 ESI+: 506 550 Rex545 ESI+: 490 551 Rex516ESI+: 319 552 Rex292 ESI+: 289 553 Rex353 ESI+: 472 554 Rex516 1H-NMR(CDCl3): 1.71-2.17 (6H, m), 2.35 (4H, m), 2.72-2.75 (4H, m), 2.99-3.02(2H, m), 3.30-3.32 (4H, m), 6.87-6.92 (1H, m), 7.87-7.99 (2H, m) 555Rex292 ESI+: 293

TABLE 84 Rex Syn Data 556 Rex353 1H-NMR (CDCl3): 1.26-1.32 (3H, m),1.56-1.65 (2H, m), 1.84-1.97 (4H, m), 2.30 (4H, m), 2.72-3.09 (12H, m),5.49 (1H, br-s), 6.90-6.95 (1H, m), 7.17-7.29 (1H, m), 7.52-7.56 (1H,m), 7.71 (1H, br-s), 10.71 (1H, br-s) 557 Rex516 1H-NMR (CDCl3): 1.59(2H, m), 1.82-1.85 (2H, m), 1.93-1.98 (2H, m), 2.27 (4H, br-s), 2.75(4H, t, J = 4.6 Hz), 2.91-2.94 (2H, m), 3.24-3.26 (4H, m), 3.95 (3H, s),6.87 (1H, d, J = 9.0 Hz), 7.70 (1H, d, J = 2.4 Hz), 7.85 (1H, dd, J =2.7, 9.0 Hz) 558 Rex292 1H-NMR (CDCl3): 1.65-2.00 (8H, m), 2.29 (4H,br-s), 2.75-2.76 (4H, m), 2.93-3.03 (6H, m), 3.83 (3H, s), 6.23-6.26(2H, m), 6.76 (1H, d, J = 8.1 Hz) 559 Rex353 1H-NMR (CDCl3): 1.57-1.98(11H, m), 2.29 (5H, m), 2.78 (4H, br-s), 2.94-2.96 (2H, m), 3.09 (4H,br-s), 3.71 (1H, br-s), 3.90 (3H, s), 5.56 (1H, br-s), 6.91 (1H, d, J =8.5 Hz), 7.13 (1H, dd, J = 2.4, 8.5 Hz), 7.36 (1H, d, J = 2.4 Hz), 7.41(1H, br-s), 10.76 (1H, br-s) 560 Rex545 ESI+: 502 561 Rex353 ESI+: 423562 Rex545 1H-NMR (CDCl3): 1.26 (6H, d, J = 6.8 Hz), 2.37 (3H, S), 2.62(4H, br-s), 3.10 (4H, br-s), 3.40-3.47 (1H, m), 5.52 (1H, br-s),6.91-6.96 (1H, m), 7.24-7.26 (1H, m), 7.53 (1H, dd, J = 2.7, 14.6 Hz),7.69 (1H, br-s), 10.70 (1H, br-s)

TABLE 85 Ex Structure 1

2

3

4

5

6

TABLE 86 Ex Structure  7

 8

 9

10

11

12

13

TABLE 87 Ex Structure 14

15

16

17

18

19

TABLE 88 Ex Structure 20

21

22

23

24

25

26

TABLE 89 Ex Structure 27

28

29

30

31

32

33

TABLE 90 Ex Structure 34

35

36

37

38

39

40

TABLE 91 Ex Structure 41

42

43

44

45

46

47

TABLE 92 Ex Structure 48

49

50

51

52

53

54

TABLE 93 Ex Structure 55

56

57

58

59

60

61

TABLE 94 Ex Structure 62

63

64

65

66

67

68

TABLE 95 Ex Structure 69

70

71

72

73

74

75

TABLE 96 Ex Structure 76

77

78

79

80

81

82

TABLE 97 Ex Structure 83

84

85

86

87

88

89

TABLE 98 Ex Structure 90

91

92

93

94

95

96

97

TABLE 99 Ex Structure  98

 99

100

101

102

103

104

TABLE 100 Ex Structure 105

106

107

108

109

110

111

112

TABLE 101 Ex Structure 113

114

115

116

117

118

119

TABLE 102 Ex Structure 120

121

122

123

124

125

126

TABLE 103 Ex Structure 127

128

129

130

131

132

133

TABLE 104 Ex Structure 134

135

136

137

138

139

140

TABLE 105 Ex Structure 141

142

143

144

145

146

147

148

TABLE 106 Ex Structure 149

150

151

152

153

154

155

156

TABLE 107 Ex Structure 157

158

159

160

161

162

163

164

165

TABLE 108 Ex Structure 166

167

168

169

170

171

172

173

TABLE 109 Ex Structure 174

175

176

177

178

179

180

181

182

TABLE 110 Ex Structure 183

184*⁵

185*⁵

186

187

188

189

190

191

TABLE 111 Ex Structure 192

193

194

195

196

197

198

199

TABLE 112 Ex Structure 200

201

202

203

204

205

206

207

TABLE 113 Ex Structure 208

209

210

211

212

213

214

215

TABLE 114 Ex Structure 216

217

218

219

220

221

222

TABLE 115 Ex Structure 223

224

225

226

227

228

229

TABLE 116 Ex Structure 230

231

232

233

234

235

236

237

TABLE 117 Ex Structure 238

239

240

241

242

243

244

245

TABLE 118 Ex Structure 246

247

248

249

250

251

252

253

TABLE 119 Ex Structure 254

255

256

257

258

259

260

261

TABLE 120 Ex Structure 262

263

264

265

266

267

268

269

TABLE 121 Ex Structure 270

271

272

273

274

275

276

277

TABLE 122 Ex Structure 278

279

280

281

282*

283

284

285

TABLE 123 Ex Structure 286

287

288

289

290

291

292

293

294

TABLE 124 Ex Structure 295

296

297

298

299

300

301*

302*

303

TABLE 125 Ex Structure 304

305

306

307

308

309

310

311

312

TABLE 126 Ex Structure 313

314*

315

316*

317*

318*

319

320

321

TABLE 127 Ex Structure 322

323

324

325

326  

  327

328

329

330

TABLE 128 Ex Structure 331

332

333

334

335

336*

337

338

TABLE 129 Ex Structure 339

340

341

342

343

344

345

346

TABLE 130 Ex Structure 347

348

349

350

351

352

TABLE 131 Ex Structure 353

354

355

356

357

358

359

360

TABLE 132 Ex Structure 361

362

363

364

365

366

367

TABLE 133 Ex Structure 368

369

370

371

372

373

374

TABLE 134 Ex Structure 375

376

377

378

379

380

381

382

TABLE 135 Ex Structure 383

384

385

386

387

388

389

TABLE 136 Ex Structure 390

391

392

393

394

395

396

397

TABLE 137 Ex Structure 398

399

400

401

402

403

404

405

TABLE 138 Ex Structure 406

407

408  

  409

410

411

412

TABLE 139 Ex Structure 413

414

415

416

417

418

419

420

TABLE 140 Ex Structure 421

422

423

424  

  425

426

427

428

TABLE 141 Ex Structure 429

430

431

432

433

434

435

436*⁶

TABLE 142 Ex Structure 437*⁶

438*⁷

439*⁷

440

441

442

443

TABLE 143 Ex Structure 444

445

446

447

448

449

450

TABLE 144 Ex Structure 451

452

453

454

455

456

457

TABLE 145 Ex Structure 458

459

460

461

462

463

464

TABLE 146 Ex Structure 465

466

467

468

469

470

471

472

TABLE 147 Ex Structure 473

474

475

476

477

478

479

480

TABLE 148 Ex Structure 481

482

483

484

485

486

487

TABLE 149 Ex Structure 488

489

490*⁸

491*⁸

492

493*⁹

494*⁹

TABLE 150 Ex Structure 495

496

497

498

499

500

TABLE 151 Ex Structure 501

502

503

504

505

506

507

TABLE 152 Ex Structure 508

509

510

511

512

513

TABLE 153 Ex Structure 514

515

516

517

518

519

TABLE 154 Ex Structure 520

521

522

523

524

525

526

TABLE 155 Ex Structure 527

528

529

530

531

532

533

TABLE 156 Ex Structure 534

535

536

537

538

539

540

TABLE 157 EX STRUCTURE 541

542

543

544

545

546

547

TABLE 158 EX STRUCTURE 548

549

550

551

552

553

TABLE 159 EX STRUCTURE 554

555

556

557

558

TABLE 160 EX STRUCTURE 559

560

561

562

563

564

TABLE 161 EX STRUCTURE 565

566

567

568

569

TABLE 162 EX STRUCTURE 570

571

572

573

574

TABLE 163 EX STRUCTURE 575

576

577

578

579

TABLE 164 EX STRUCTURE 580

581

582

TABLE 165 Ex Syn Data 1 Ex4 ESI+: 451 2 Ex4 ESI+: 463 3 Ex4 ESI+: 477 4Ex4 ESI+: 491 5 Ex4 ESI+: 493 6 Ex4 ESI+: 509 7 Ex4 ESI+: 423 8 Ex4ESI+: 449 9 Ex4 ESI+: 477 10 Ex4 FAB+: 450 11 Ex4 FAB+: 450 12 Ex4 FAB+:449 13 Ex4 ESI+: 449 14 Ex4 ESI+: 449 15 Ex4 ESI+: 449 16 Ex4 ESI+: 43617 Ex4 ESI+: 436 18 Ex4 ESI+: 436 19 Ex19 ESI+: 449 20 Ex4 ESI+: 435 21Ex4 ESI+: 435 22 Ex4 ESI+: 463 23 Ex37 ESI+: 639 24 Ex4 ESI+: 435 25 Ex4ESI+: 435 26 Ex4 ESI+: 421 27 Ex4 ESI+: 421 28 Ex37 ESI+: 535 29 Ex29ESI+: 435 30 Ex405 FAB+: 477 31 Ex31 FAB+: 513 32 Ex4 ESI+: 477 33 Ex4ESI+: 477 34 Ex4 ESI+: 372 35 Ex4 FAB+: 436 36 Ex4 ESI+: 400 37 Ex37ESI+: 414 38 Ex4 ESI+: 428 39 Ex4 ESI+: 449 40 Ex4 ESI+: 463 41 Ex4ESI+: 437 42 Ex4 ESI+: 436 43 Ex4 ESI−: 400 44 Ex4 ESI+: 463 45 Ex4ESI+: 449 46 Ex4 ESI+: 464 47 Ex4 ESI+: 392 48 Ex4 ESI+: 450 49 Ex4ESI+: 426 50 Ex4 ESI+: 468 51 Ex4 ESI+: 454 52 Ex4 ESI+: 489 53 Ex4FAB+: 388 54 Ex4 FAB+: 450 55 Ex4 ESI+: 449 56 Ex4 ESI+: 470 57 Ex4ESI+: 456 58 Ex4 ESI+: 468 59 Ex4 ESI+: 442 60 Ex4 ESI+: 414 61 Ex4ESI+: 484 62 Ex4 ESI+: 470 63 Ex4 ESI+: 492 64 Ex4 ESI+: 504 65 Ex4ESI+: 448 66 Ex4 ESI+: 490

TABLE 166 Ex Syn Data 67 Ex4 ESI+: 408 68 Ex4 ESI+: 434 69 Ex4 FAB+: 38270 Ex4 FAB+: 409 71 Ex4 ESI+: 381 72 Ex4 FAB+: 410 73 Ex4 ESI+: 478 74Ex4 ESI+: 506 75 Ex4 ESI+: 518 76 Ex4 ESI+: 492 77 Ex4 ESI+: 464 78 Ex4ESI+: 502 79 Ex4 ESI+: 476 80 Ex4 ESI+: 482 81 Ex4 ESI+: 456 82 Ex4ESI+: 428 83 Ex4 ESI+: 469, 471 84 Ex84 ESI+: 447 85 Ex84 ESI+: 433 86Ex84 ESI+: 434 87 Ex4 ESI+: 434 88 Ex4 ESI+: 392 89 Ex84 ESI+: 400 90Ex4 ESI+: 372 91 Ex4 ESI+: 520 92 Ex4 ESI+: 508 93 Ex4 ESI+: 488 94 Ex4ESI+: 434 95 Ex4 ESI+: 462 96 Ex4 ESI+: 446 97 Ex4 ESI+: 472 98 Ex4ESI+: 474 99 Ex4 ESI+: 460 100 Ex4 ESI+: 392 101 Ex84 FAB+: 419 102 Ex84FAB+: 475 103 Ex84 FAB+: 448 104 Ex4 ESI+: 426 105 Ex4 ESI+: 426 106 Ex4ESI+: 434 107 Ex4 ESI+: 422 108 Ex84 ESI+: 433 109 Ex84 ESI+: 448 110Ex84 ESI+: 448 111 Ex84 FAB+: 406 112 Ex146 ESI+: 420 113 Ex4 ESI+: 436114 Ex4 ESI+: 358 115 Ex4 ESI+: 392 116 Ex4 ESI+: 392 117 Ex84 ESI+: 423118 Ex4 ESI+: 494 119 Ex4 ESI+: 508 120 Ex4 ESI+: 482 121 Ex4 ESI+: 428122 Ex4 ESI+: 484 123 Ex4 ESI+: 468 124 Ex4 ESI+: 414 125 Ex4 ESI+: 468126 Ex4 ESI+: 418 127 Ex4 ESI+: 486 128 Ex4 ESI+: 482 129 Ex4 ESI+: 522130 Ex4 ESI+: 480 131 Ex4 FAB+: 508 132 Ex4 ESI+: 468

TABLE 167 Ex Syn Data 133 Ex4 FAB+: 414 134 Ex4 ESI+: 522 135 Ex4 FAB+:534 136 Ex4 FAB+: 444 137 Ex4 ESI+: 498 138 Ex4 ESI+: 482 139 Ex4 FAB+:428 140 Ex4 ESI+: 536 141 Ex4 ESI+: 460 142 Ex4 ESI+: 432 143 Ex4 ESI+:488 144 Ex4 ESI+: 474 145 Ex4 ESI+: 460 146 Ex146 ESI+: 468 147 Ex84ESI+: 486 148 Ex84 ESI+: 448 149 Ex84 ESI+: 434 150 Ex84 ESI+: 427 151Ex84 ESI+: 535 152 Ex84 ESI+: 427 153 Ex84 ESI+: 427 154 Ex4 ESI+: 448155 Ex84 ESI+: 447 156 Ex84 ESI+: 443 157 Ex84 ESI+: 433 158 Ex84 ESI+:433 159 Ex159 ESI+: 440 160 Ex84 ESI+: 427 161 Ex84 ESI+: 481 162 Ex84ESI+: 427 163 Ex84 ESI+: 447 164 Ex84 ESI+: 406 165 Ex146 ESI+: 448 166Ex84 ESI+: 434 167 Ex84 ESI+: 461 168 Ex84 ESI+: 497 169 Ex84 ESI+: 461170 Ex84 ESI+: 448 171 Ex84 FAB+: 431 172 Ex84 FAB+: 447 173 Ex4 FAB−:405 174 Ex84 FAB−: 404 175 Ex84 FAB+: 479 176 Ex84 FAB+: 413 177 Ex84ESI+: 454 178 Ex146 ESI+: 407 179 Ex84 ESI+: 454 180 Ex159 ESI+: 488 181Ex181 ESI+: 484, 486 182 Ex84 ESI+: 357 183 Ex84 ESI+: 441 184 Ex84ESI+: 469 185 Ex84 ESI+: 469 186 Ex84 ESI+: 441 187 Ex84 ESI+: 427 188Ex84 ESI+: 346 189 Ex84 ESI+: 431 190 Ex190 ESI+: 532 191 Ex84 ESI+: 371192 Ex146 APCI/ESI+: 371 193 Ex84 ESI+: 434 194 Ex84 ESI+: 434 195 Ex196ESI+: 419 196 Ex196 ESI+: 433 197 Ex196 ESI+: 447 198 Ex196 ESI+: 447

TABLE 168 Ex Syn Data 199 Ex196 ESI+: 461 200 Ex196 ESI+: 515 201 Ex196ESI+: 523 202 Ex196 ESI+: 447 203 Ex196 ESI+: 475 204 Ex196 ESI+: 491205 Ex196 ESI+: 433 206 Ex196 ESI+: 433 207 Ex196 ESI+: 418 208 Ex196ESI+: 448 209 Ex196 ESI+: 448 210 Ex196 ESI+: 496 211 Ex196 ESI+: 405212 Ex196 ESI+: 405 213 Ex196 ESI+: 419 214 Ex196 ESI+: 495 215 Ex196ESI+: 495 216 Ex196 ESI+: 419 217 Ex196 ESI+: 447 218 Ex196 ESI+: 420219 Ex196 ESI+: 434 220 Ex196 ESI+: 438 221 Ex196 ESI+: 391 222 Ex196ESI+: 405 223 Ex196 ESI+: 473 224 Ex196 ESI+: 447 225 Ex196 ESI+: 447226 Ex196 ESI+: 449 227 Ex196 ESI+: 463 228 Ex196 ESI+: 515 229 Ex196ESI+: 523 230 Ex196 ESI+: 433 231 Ex196 ESI+: 433 232 Ex196 ESI+: 433233 Ex196 ESI+: 433 234 Ex196 ESI+: 433 235 Ex196 ESI+: 434 236 Ex196ESI+: 434 237 Ex196 ESI+: 436 238 Ex196 ESI+: 448 239 Ex196 ESI+: 448240 Ex196 ESI+: 447 241 Ex196 ESI+: 447 242 Ex196 ESI+: 420 243 Ex196ESI+: 420 244 Ex196 ESI+: 405 245 Ex196 ESI+: 406 246 Ex196 ESI+: 462247 Ex196 ESI+: 476 248 Ex196 ESI+: 447 249 Ex196 ESI+: 462 250 Ex196ESI+: 463 251 Ex196 ESI+: 448 252 Ex196 ESI+: 433 253 Ex196 ESI+: 447254 Ex196 ESI+: 434 255 Ex196 ESI+: 379 256 Ex196 ESI+: 393 257 Ex196ESI+: 407 258 Ex196 ESI+: 421 259 Ex196 ESI+: 421 260 Ex196 ESI+: 421261 Ex196 ESI+: 407 262 Ex196 ESI+: 380 263 Ex196 ESI+: 394 264 Ex196ESI+: 408

TABLE 169 Ex Syn Data 265 Ex196 ESI+: 394 266 Ex196 ESI+: 410 267 Ex196ESI+: 394 268 Ex196 ESI+: 438 269 Ex196 ESI+: 419 270 Ex196 ESI+: 481271 Ex196 ESI+: 406 272 Ex196 ESI+: 434 273 Ex196 ESI+: 421 274 Ex196ESI+: 394 275 Ex196 ESI+: 442 276 Ex196 ESI+: 413 277 Ex196 ESI+: 426278 Ex196 ESI+: 456 279 Ex196 ESI+: 427 280 Ex196 ESI+: 528 281 Ex84ESI+: 427 282 Ex84 ESI+: 455 283 Ex84 ESI+: 370 284 Ex84 ESI+: 567 285Ex84 ESI+: 463 286 Ex84 ESI+: 483 287 Ex84 ESI+: 447 288 Ex84 ESI+: 443289 Ex84 ESI+: 463 290 Ex84 ESI+: 535 291 Ex84 ESI+: 427 292 Ex84 ESI+:396 293 Ex84 ESI+: 414 294 Ex84 ESI+: 525 295 Ex84 ESI+: 549 296 Ex146ESI+: 448 297 Ex84 ESI+: 433 298 Ex84 ESI+: 407 299 Ex84 ESI+: 378 300Ex84 ESI+: 404 301 Ex84 ESI+: 461 302 Ex302 ESI+: 489 303 Ex84 ESI+: 424304 Ex84 ESI+: 396 305 Ex84 ESI+: 412 306 Ex84 ESI+: 407 307 Ex84 ESI+:547 308 Ex84 ESI+: 429 309 Ex309 ESI+: 399 310 Ex310 ESI+: 453 311 Ex84ESI+: 549 312 Ex84 ESI+: 428 313 Ex84 ESI+: 496 314 Ex84 ESI+: 494 315Ex84 ESI+: 427 316 Ex84 ESI+: 480 317 Ex84 ESI+: 466 318 Ex84 ESI+: 494319 Ex84 ESI+: 401 320 Ex84 ESI+: 447 321 Ex84 ESI+: 440 322 Ex302 ESI+:468 323 Ex146 ESI+: 502 324 Ex84 ESI+: 440 325 Ex84 ESI+: 454 326 Ex84ESI+: 526 327 Ex84 ESI+: 414 328 Ex84 ESI+: 410 329 Ex84 ESI+: 441 330Ex84 ESI+: 414

TABLE 170 Ex Syn Data 331 Ex84 ESI+: 409 332 Ex84 ESI+: 508 333 Ex84ESI+: 385 334 Ex84 ESI+: 482 335 Ex84 ESI+: 480 336 Ex84 ESI+: 468 337Ex84 ESI+: 453 338 Ex84 ESI+: 512 339 Ex84 ESI+: 484 340 Ex84 ESI+: 567341 Ex84 ESI+: 537 342 Ex84 ESI+: 466 343 Ex343 ESI+: 468 344 Ex84 ESI+:512 345 Ex159 ESI+: 546 346 Ex381 ESI+: 446 347 Ex84 ESI+: 454 348 Ex84ESI+: 581 349 Ex84 ESI+: 581 350 Ex84 ESI+: 570 351 Ex146 ESI+: 549 352Ex84 ESI+: 449 353 Ex84 ESI+: 463 354 Ex84 ESI+: 522 355 Ex84 ESI+: 484356 Ex84 ESI+: 539 357 Ex84 ESI+: 441 358 Ex381 ESI+: 439 359 Ex84 ESI+:439 360 Ex84 ESI+: 636 361 Ex84 ESI+: 469 362 Ex84 ESI+: 468 363 Ex84ESI+: 538 364 Ex84 ESI+: 560 365 Ex84 ESI+: 455 366 Ex84 ESI+: 476 367Ex84 ESI+: 455 368 Ex84 ESI+: 442 369 Ex84 ESI+: 477 370 Ex146 ESI+: 605371 Ex84 ESI+: 538 372 Ex84 ESI+: 560 373 Ex84 ESI+: 631 374 Ex84 ESI+:456 375 Ex84 ESI+: 455 376 Ex84 ESI+: 552 377 Ex84 ESI+: 468 378 Ex84ESI+: 551 379 Ex84 ESI+: 464 380 Ex84 ESI+: 442 381 Ex381 ESI+: 469 382Ex84 ESI+: 569 383 Ex84 ESI+: 484 384 Ex84 ESI+: 522 385 Ex84 ESI+: 617386 Ex84 ESI+: 644 387 Ex84 ESI+: 453 388 Ex343 ESI+: 619 389 Ex343ESI+: 646 390 Ex84 ESI−: 488 391 Ex84 ESI+: 482 392 Ex84 ESI+: 565 393Ex84 ESI+: 540 394 Ex381 ESI+: 440 395 Ex302 ESI+: 522 396 Ex302 ESI+:524

TABLE 171 Ex Syn Data 397 Ex84 ESI+: 543 398 Ex84 ESI−: 479 399 Ex84ESI+: 562 400 Ex84 ESI+: 434, 436 401 Ex84 ESI+: 484 402 Ex84 ESI+: 536403 Ex84 ESI+: 537 404 Ex84 ESI+: 522 405 Ex405 ESI+: 481 406 Ex84 ESI+:536 407 Ex84 ESI+: 536 408 Ex84 ESI+: 536 409 Ex84 ESI+: 550 410 Ex84ESI+: 484 411 Ex84 ESI+: 441 412 Ex84 ESI+: 456 413 Ex84 ESI+: 468 414Ex84 ESI+: 482 415 Ex31 ESI+: 518 416 Ex302 ESI+: 482 417 Ex302 ESI+:540 418 Ex84 ESI+: 607 419 Ex381 ESI+: 508 420 Ex84 ESI+: 554 421 Ex381ESI+: 454 422 Ex146 ESI+: 535 423 Ex302 ESI+: 590 424 Ex302 ESI+: 536425 Ex302 ESI+: 550 426 Ex302 ESI+: 496 427 Ex84 ESI+: 496 428 Ex84ESI+: 555 429 Ex84 ESI+: 576 430 Ex84 ESI+: 518 431 Ex302 ESI+: 521 432Ex84 ESI+: 553 433 Ex381 ESI+: 453 434 Ex31 ESI+: 531 435 Ex84 ESI+: 564436 Ex436 ESI+: 550 437 Ex436 ESI+: 550 438 Ex438 ESI+: 655 439 Ex438ESI+: 655 440 Ex84 ESI+: 453 441 Ex84 ESI+: 483 442 Ex84 ESI+: 488 443Ex84 ESI+: 483 444 Ex84 ESI+: 566 445 Ex84 ESI+: 544 446 Ex84 ESI+: 597447 Ex302 ESI+: 602 448 Ex84 ESI+: 550 449 Ex302 ESI+: 642 450 Ex302ESI−: 636 451 Ex302 ESI+: 467 452 Ex84 ESI+: 482 453 Ex84 ESI+: 609 454Ex84 ESI+: 482 455 Ex84 ESI+: 607 456 Ex84 ESI+: 536 457 Ex84 ESI+: 566458 Ex84 APCI/ESI+: 511 459 Ex84 ESI+: 581 460 Ex534 ESI+: 507 461 Ex84ESI+: 522 462 Ex405 ESI+: 549

TABLE 172 Ex Syn Data 463 Ex405 ESI+: 641 464 Ex302 ESI+: 644 465 Ex84ESI+: 561 466 Ex84 ESI+: 565 467 Ex84 ESI+: 570 468 Ex381 ESI+: 470 469Ex302 ESI+: 495 470 Ex302 ESI+: 535 471 Ex302 ESI+: 449 472 Ex84 ESI+:449 473 Ex84 ESI+: 607 474 Ex381 ESI+: 507 475 Ex84 ESI+: 482 476 Ex84ESI+: 471 477 Ex84 ESI+: 469 478 Ex84 ESI+: 567 479 Ex84 ESI+: 554 480Ex84 ESI+: 469 481 Ex84 ESI+: 499 482 Ex159 ESI+: 533 483 Ex84 ESI+: 565484 Ex84 ESI+: 511 485 Ex84 ESI+: 547 486 Ex84 ESI+: 530 487 Ex84 ESI+:525 488 Ex302 ESI+: 512 489 Ex302 ESI+: 552 490 Ex84 ESI+: 579 491 Ex84ESI+: 579 492 Ex302 ESI+: 608 493 Ex84 ESI+: 593 494 Ex84 ESI+: 593 495Ex495 ESI+: 489 496 Ex84 FAB+: 553 497 Ex84 ESI+: 553 498 Ex84 ESI+: 540499 Ex499 ESI+: 573 500 Ex84 FAB+: 540 501 Ex84 ESI+: 485 502 Ex84 ESI+:499 503 Ex84 ESI+: 512 504 Ex84 ESI+: 498 505 Ex84 ESI+: 567 506 Ex84ESI+: 551 507 Ex84 APCI/ESI+: 626 508 Ex508 APCI/ESI+: 446 509 Ex84ESI+: 539 510 Ex84 ESI+: 567 511 Ex84 ESI+: 554 512 Ex84 ESI+: 537 513Ex84 ESI+: 611 514 Ex302 ESI+: 521 515 Ex84 ESI+: 532 516 Ex84 ESI+: 568517 Ex146 ESI+: 651 518 Ex381 ESI+: 551 519 Ex84 ESI+: 572 520 Ex84ESI+: 663 521 Ex84 ESI+: 594 522 Ex84 ESI+: 608 523 Ex84 ESI+: 494 524Ex84 ESI+: 514 525 Ex84 ESI+: 561 526 Ex84 ESI+: 511 527 Ex84 ESI+: 644528 Ex84 ESI+: 547

TABLE 173 Ex Syn Data 529 Ex84 ESI+: 525 530 Ex84 ESI+: 483 531 Ex84ESI+: 499 532 Ex159 ESI+: 517 533 Ex159 ESI+: 533 534 Ex534 ESI+: 536535 Ex84 ESI+: 564 536 Ex495 ESI+: 473 537 Ex495 ESI+: 489 538 Ex499ESI+: 557 539 Ex499 ESI+: 573 540 Ex84 ESI+: 573 541 Ex84 ESI+: 559 542Ex84 APCI/ESI+: 613 543 Ex84 ESI+: 613 544 Ex84 ESI+: 550 545 Ex84 ESI+:440 546 Ex84 ESI+: 523 547 Ex84 ESI+: 553 548 Ex84 ESI+: 470 549 Ex343ESI+: 537 550 Ex84 ESI+: 458 551 Ex302 ESI+: 553 552 Ex302 ESI+: 523 553Ex84 ESI+: 484 554 Ex84 ESI+: 454 555 Ex84 ESI+: 472 556 Ex84 ESI+: 567557 Ex84 ESI+: 541 558 Ex84 ESI+: 537 559 Ex84 ESI+: 555 560 Ex84APCI/ESI+: 535 561 Ex84 ESI+: 556 562 Ex381 ESI+: 456 563 Ex84 ESI+: 524564 Ex381 ESI+: 426 565 Ex84 ESI+: 454 566 Ex84 ESI+: 537 567 Ex343ESI+: 468 568 Ex146 ESI+: 605 569 Ex84 ESI+: 551 570 Ex343 ESI+: 619 571Ex84 ESI+: 565 572 Ex302 ESI+: 496 573 Ex84 ESI+: 565 574 Ex84 ESI+: 537575 Ex499 ESI+: 557 576 Ex84 ESI+: 523 577 Ex84 ESI+: 553 578 Ex343ESI+: 537 579 Ex84 ESI+: 441 580 Ex84 ESI+: 484 581 Ex84 ESI+: 454 582Ex84 ESI+: 537

TABLE 174 Ex Data 86 ¹H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.8 Hz),1..33-1.50 (4H, m), 1.79-1.95 (4H, m), 2.60 (2H, q, J = 7.8 Hz), 3.21(3H, s), 3.37-3.49 (1H, m), 3.89-4.01 (1H, m), 4.54 (1H, d, J = 4.4 Hz),6.76 (1H, d, J = 7.9 Hz), 7.33-7.42 (1H, m), 7.44-7.57 (2H, m),7.58-7.65 (1H, m), 7.96-8.03 (1H, m), 8.15-8.21 (1H, m), 11.59 (1H, s).110 ¹H-NMR (DMSO-d6): 1.13-1.25 (6H, m), 1.46-1.64 (6H, m), 1.79-1.91(2H, m), 2.61 (2H, q, J = 7.4 Hz), 3.21 (3H, s), 3.94-4.09 (1H, m), 4.26(1H, s), 6.72 (1H, d, J = 7.9 Hz), 7.33-7.42 (1H, m), 7.44-7.58 (2H, m),7.59-7.66 (1H, m), 7.98-8.04 (1H, m), 8.16-8.20 (1H, m), 11.58 (1H, s).284 ¹H-NMR (CDCl3): 1.26-1.36 (5H, m), 1.48-1.56 (2H, m), 1.68-1.76 (2H,m), 1.95 (2H, d, J = 11.6 Hz), 2.08 (2H, d, J = 10.4 Hz), 2.26 (2H, d, J= 11.6 Hz), 2.30 (3H, s), 2.30-2.73 (13H, m), 3.64-3.74 (4H, m),3.93-3.97 (4H, m), 4.52 (1H, d, J = 7.2 Hz), 5.13 (1H, br-s), 6.50 (1H,dd, J = 2.4 Hz, 9.2 Hz), 6.58 (1H, d, J = 2.4 Hz), 7.46 (1H, br-s), 8.39(1H, d, J = 8.8 Hz), 10.98 (1H, s). 325 ¹H-NMR (DMSO-d6): 1.17 (3H, t, J= 7.4 Hz), 1.22-1.48 (4H, m), 1.84-2.00 (4H, m), 2.25 (3H, s), 2.44-2.59(6H, m), 3.00-3.12 (4H, m), 3.43 (1H, m), 3.80 (1H, m), 4.56 (1H, d, J =4.7 Hz), 6.63 (1H, d, J = 8.0 Hz), 6.87 (2H, d, J = 9.2 Hz), 7.13 (1H,br), 7.47 (1H, br), 7.51 (2H, d, J = 9.2 Hz), 10.9 (1H, s). 328 ¹H-NMR(CDCl3): 1.25-1.67 (7H, m), 2.04 (2H, m), 2.17-2.22 (2H, m), 2.48-2.55(2H, m), 3.72 (1H, m), 4.03 (3H, s), 4.05 (1H, m), 4.60 (1H, m), 5.19(1H, m), 7.44 (1H, m), 7.51 (1H, m), 7.62 (1H, m), 7.78 (1H, s), 7.88(1H, s), 11.14 (1H, br-s). 340 ¹H-NMR (CDCl3): 1.22-1.54 (7H, m),1.74-1.94 (4H, m), 2.01-2.10 (2H, m), 2.16-2.26 (2H, m), 2.30 (3H, s),2.32-2.74 (13H, m), 3.50 (2H, d, J = 11.4 Hz), 3.65-3.76 (1H, m), 3.87(3H, s), 3.92-4.03 (1H, m), 4.52 (1H, d, J = 7.3 Hz), 5.12 (1H, br-s),6.71 (1H, s), 6.84-6.90 (2H, m), 7.45-7.55 (2H, m), 10.74 (1H, s).

TABLE 175 Ex Data 341 ¹H-NMR (DMSO-d6): 1.17 (3H, t, J = 7.4 Hz),1.21-1.60 (6H, m), 1.75-2.00 (6H, m), 2.14 (3H, s), 2.20-2.72 (13H, m),3.43 (1H, m), 3.58 (2H, m), 3.80 (1H, m), 4.57 (1H, d, J = 4.4 Hz), 6.63(1H, d, J = 7.3 Hz), 6.86 (2H, d, J = 8.7 Hz), 7.13 (1H, br-s),7.40-7.60 (3H, m), 10.92 (1H, s). 343 ¹H-NMR (DMSO-d6): 1.14 (6H, d, J =6.6 Hz), 1.21-1.48 (4H, m), 1.85-1.98 (4H, m), 2.22 (3H, s), 2.41-2.48(4H, m), 2.99-3.18 (5H, m), 3.37-3.48 (1H, m), 3.74-3.87 (1H, m), 4.56(1H, d, J = 4.7 Hz), 6.67 (1H, d, J = 7.6 Hz), 6.86 (2H, d, J = 9.0 Hz),7.11-7.18 (1H, m), 7.40-7.47 (1H, m), 7.50 (2H, d, J = 9.0 Hz), 10.91(1H, s) 347 ¹H-NMR (DMSO-d6): 1.10-1.49 (7H, m), 1.80-1.96 (4H, m), 2.22(3H, s), 2.40-2.61 (6H, m), 3.06-3.18 (4H, m), 3.43 (1H, m), 3.86 (1H,m), 4.56 (1H, d, J = 4.3 Hz), 6.57 (1H, m), 6.63 (1H, d, J = 7.6 Hz),6.91 (1H, m), 7.10 (1H, m), 7.18 (1H, br), 7.29 (1H, m), 7.51 (1H,br-s), 11.09 (1H, s). 354 ¹H-NMR (DMSO-d6): 1.12-1.32 (5H, m), 1.36-1.50(2H, m), 1.78-1.96 (4H, m), 2.22 (3H, s), 2.35-2.63 (6H, m), 2.78-2.88(4H, m), 3.41 (1H, m), 3.87 (1H, m), 4.55 (1H, d, J = 3.9 Hz), 6.68 (1H,d, J = 7.9 Hz), 7.27 (1H, br-s), 7.46 (1H, d, J = 8.7 Hz), 7.56 (1H,br-s), 7.61 (1H, m), 8.18 (1H, m), 11.37 (1H, s) 355 ¹H-NMR (DMSO-d6):1.10-1.32 (5H, m), 1.32-1.50 (2H, m), 1.82-1.96 (4H, m), 2.21 (3H, s),2.35-2.60 (6H, m), 2.84-2.99 (4H, m), 3.42 (1H, m), 3.81 (3H, s), 3.87(1H, m), 4.56 (1H, d, J = 4.6 Hz), 6.61 (1H, d, J = 7.8 Hz), 6.79 (1H,d, J = 8.6 Hz), 7.09 (1H, d, J = 2.2 Hz), 7.16 (1H, br-s), 7.24 (1H, dd,J = 8.6, 2.2 Hz), 7.49 (1H, br-s), 11.03 (1H, s) 357 ¹H-NMR (DMSO-d6):1.17 (3H, t, J = 7.4 Hz), 1.21-1.48 (4H, m), 1.84-2.00 (4H, m), 2.55(2H, q, J = 7.4 Hz), 3.00-3.06 (4H, m), 3.42 (1H, m), 3.69-3.86 (5H, m),4.58 (1H, d, J = 4.8 Hz), 6.65 (1H, d, J = 7.4 Hz), 6.84-6.90 (2H, m),7.16 (1H, m), 7.44-7.56 (3H, m), 10.95 (1H, s)

TABLE 176 Ex Data 370 ¹H-NMR (DMSO-d6): 1.10-1.32 (5H, m), 1.36-1.58(4H, m), 1.75-1.93 (6H, m), 2.14 (3H, s), 2.22-2.38 (4H, m), 2.40-2.62(5H, m), 2.65-2.78 (2H, m), 2.87-2.97 (2H, m), 3.20-3.48 (3H, m), 3.87(1H, m), 4.56 (1H, d, J = 3.9 Hz), 6.67 (1H, d, J = 7.9 Hz), 7.27 (1H,br-s), 7.42 (1H, d, J = 8.7 Hz), 7.55 (1H, br-s), 7.62 (1H, m), 8.15(1H, m), 11.37 (1H, s) 377 ¹H-NMR (CDCl3): 1.24-1.35 (5H, m), 1.43-1.50(2H, m), 2.04-2.07 (2H, m), 2.17-2.24 (2H, m), 2.32 (3H, s), 2.36 (3H,s), 2.47 (2H, q, J = 7.1 Hz), 2.58 (4H, br-s), 2.92-2.94 (4H, m), 3.70(1H, m), 3.95-3.99 (1H, m), 4.51 (1H, d, J = 7.1 Hz), 5.11 (1H, br-s),6.98 (1H, d, J = 8.3 Hz), 7.48-7.52 (3H, m), 10.70 (1H, br-s). 378¹H-NMR (CDCl3): 1.23-1.32 (5H, m), 1.45-1.72 (4H, m), 1.92-2.08 (4H, m),2.17-2.30 (8H, m), 2.45-2.67 (13H, m), 3.15 (2H, m), 3.71-3.73 (1H, m),3.98 (1H, m), 4.51 (1H, d, J = 7.1 Hz), 5.11 (1H, m), 6.93 (1H, d, J =8.5 Hz), 7.46-7.52 (3H, m), 10.70 (1H, br-s). 383 ¹H-NMR (DMSO-d6): 1.17(3H, t, J = 7.4 Hz), 1.20-1.32 (2H, m), 1.35-1.48 (2H, m), 1.81-1.93(4H, m), 2.22 (3H, s), 2.40-2.60 (6H, m), 2.94-3.04 (4H, m), 3.36-3.47(1H, m), 3.76 (3H, s), 3.80-3.93 (1H, m), 4.53 (1H, d, J = 4.3 Hz), 6.58(1H, d, J = 7.7 Hz), 6.82 (1H, d, J = 8.6 Hz), 6.86 (1H, d, J = 2.0 Hz),7.10-7.17 (1H, m), 7.37 (1H, dd, J = 2.0, 8.6 Hz), 7.44-7.51 (1H, m),10.93 (1H, s) 387 ¹H-NMR (DMSO-d6): 1.17 (3H, t, J = 7.3 Hz), 1.22-1.52(4H, m), 1.54-1.78 (4H, m), 1.85-2.03 (6H, m), 2.18 (3H, s), 2.40 (1H,m), 2.56 (2H, q, J = 7.3 Hz), 2.80-2.90 (2H, m), 3.43 (1H, m), 3.82 (1H,m), 4.58 (1H, d, J = 4.7 Hz), 6.70 (1H, d, J = 7.3 Hz), 7.13 (2H, d, J =8.5 Hz), 7.19 (1H, br), 7.50 (1H, br), 7.59 (2H, d, J = 8.5 Hz), 11.11(1H, s)

TABLE 177 Ex Data 388 1H-NMR (DMSO-d6): 1.15 (6H, d, J = 6.7 Hz),1.18-1.33 (2H, m), 1.36-1.59 (4H, m), 1.75-1.91 (6H, m), 2.14 (3H, s),2.21-2.56 (9H, m), 2.64-2.79 (2H, m), 2.87-2.98 (2H, m), 3.09-3.21 (1H,m), 3.36-3.48 (1H, m), 3.79-3.96 (1H, m), 4.56 (1H, d, J = 3.9 Hz), 6.72(1H, d, J = 7.3 Hz), 7.22-7.33 (1H, m), 7.42 (1H, d, J = 9.0 Hz),7.48-7.56 (1H, m), 7.58-7.66 (1H, m), 8.14 (1H, d, J = 2.3 Hz), 11.35(1H, s). 391 1H-NMR (CDCl3): 1.26-1.30 (6H, m), 1.49-1.76 (6H, m),1.97-2.01 (2H, m), 2.30 (3H, s), 2.36 (3H, s), 2.48 (2H, q, J = 7.3 Hz),2.59 (4H, br-s), 2.91-2.94 (4H, m), 3.73-3.97 (1H, m), 4.61 (1H, d, J =7.5 Hz), 5.10 (1H, br-s), 6.96 (1H, d, J = 8.5 Hz), 7.48-7.53 (3H, m),10.69 (1H, br-s). 392 1H-NMR (CDCl3): 1.26-1.32 (6H, m), 1.54-1.76 (8H,m), 1.92-2.00 (4H, m), 2.28 (3H, s), 2.30 (3H, s), 2.47 (2H, q, J = 7.3Hz), 2.60-2.66 (11H, m), 3.12-3.15 (2H, m), 3.94-3.97 (1H, m), 4.60 (1H,d, J = 7.3 Hz), 5.10 (1H, br-s), 6.91 (1H, d, J = 8.5 Hz), 7.41-7.71(3H, m), 10.69 (1H, br-s). 399 1H-NMR (CDCl3): 0.13-0.16 (2H, m),0.52-0.57 (2H, m), 0.92 (1H, m), 1.24-1.58 (7H, m), 2.03 (2H, m), 2.18(2H, m), 2.33 (2H, m), 2.49 (2H, q, J = 7.6 Hz), 2.68 (4H, br-s), 2.98(4H, m), 3.66 (1H, m), 4.00 (1H, m), 4.56 (1H, d, J = 7.6 Hz), 5.16 (1H,m), 7.34 (1H, d, J = 8.8 Hz), 7.51 (1H, m), 7.62 (1H, dd, J = 8.8, 2.4Hz), 8.18 (1H, d, J = 2.4 Hz), 10.96 (1H, br-s). 406 1H-NMR (CDCl3):1.29 (3H, t, J = 7.3 Hz), 1.43-1.52 (4H, m), 1.85-1.90 (1H, m),2.01-2.04 (2H, m), 2.12-2.18 (3H, m), 2.29 (6H, s), 2.46 (2H, q, J = 7.3Hz), 2.86-2.90 (1H, m), 3.16-3.37 (4H, m), 3.66 (1H, m), 3.97-4.00 (1H,m), 4.53 (1H, d, J = 7.6 Hz), 5.15 (1H, br-s), 7.11 (1H, d, J = 8.8 Hz),7.48-7.55 (2H, m), 8.15 (1H, d, J = 2.4 Hz), 10.84 (1H, br-s).

TABLE 178 Ex Data 426 1H-NMR (CDCl3): 1.11 (6H, d, J = 6.3 Hz),1.24-1.32 (5H, m), 1.39-1.52 (2H, m), 2.05-2.07 (2H, m), 2.20-2.23 (2H,m), 2.32 (3H, s), 2.47 (2H, q, J = 7.3 Hz), 2.70-2.78 (5H, m), 2.94-2.96(5H, m), 3.66-3.71 (1H, m), 3.93-3.98 (1H, m), 4.54 (1H, d, J = 7.1 Hz),5.19 (1H, br-s), 6.99 (1H, d, J = 8.5 Hz), 7.44-7.55 (3H, m), 10.68 (1H,br-s). 459 1H-NMR (CDCl3): 1.20-1.54 (10H, m), 1.70-2.09 (6H, m), 2.21(2H, d, J = 11.4 Hz), 2.29 (3H, s), 2.32-2.73 (13H, m), 3.54 (2H, d, J =11.6 Hz), 3.63-3.75 (1H, m), 3.92-4.40 (1H, m), 4.07 (2H, q, J = 6.9Hz), 4.52 (1H, d, J = 7.3 Hz), 5.12 (1H, br-s), 6.84 (1H, d, J = 8.7Hz), 6.93 (1H, d, J = 2.1 Hz), 7.26 (1H, s), 7.47 (2H, dd, J = 8.5, 2.2Hz), 10.72 (1H, s). 466 1H-NMR (CDCl3): 1.26-2.74 (38H, m), 3.12-3.15(2H, m), 4.08 (1H, m), 4.63 (1H, d, J = 6.8 Hz), 5.14 (1H, br-s), 6.93(1H, d, J = 8.1 Hz), 7.49-7.54 (3H, m), 10.71 (1H, br-s). 490 1H-NMR(CDCl3): 0.96 (3H, t, J = 7.6 Hz), 1.25-2.71 (36H, m), 3.11-3.15 (2H,m), 3.95-3.97 (1H, m), 4.61 (1H, d, J = 7.3 Hz), 5.09 (1H, br-s), 6.91(1H, d, J = 8.8 Hz), 7.40-7.56 (3H, m), 10.68 (1H, br-s). 491 1H-NMR(CDCl3): 0.92 (3H, t, J = 7.3 Hz), 1.26-2.71 (36H, m), 3.12-3.15 (2H,m), 4.11-4.17 (1H, m), 4.64 (1H, d, J = 6.8 Hz), 5.13 (1H, br-s), 6.93(1H, d, J = 8.1 Hz), 7.49-7.54 (3H, m), 10.71 (1H, br-s). 493 1H-NMR(CDCl3): 0.96 (6H, d, J = 7.1 Hz), 1.26-1.30 (5H, m), 1.56-2.69 (30H,m), 3.13 (2H, d, J = 10.5 Hz), 3.94 (1H, m), 4.61 (1H, d, J = 7.8 Hz),5.09 (1H, br-s), 6.91 (1H, d, J = 8.5 Hz), 7.40 (1H, d, J = 6.6 Hz),7.48 (1H, br-s), 7.56 (1H, d, J = 2.7 Hz), 10.67 (1H, br-s). 494 1H-NMR(CDCl3): 0.95 (6H, d, J = 6.8 Hz), 1.25-3.18 (37H, m), 3.64-3.67 (1H,m), 4.72 (1H, d, J = 7.1 Hz), 5.12 (1H, br-s), 6.92 (1H, d, J = 8.5 Hz),7.48-7.54 (3H, m), 10.73 (1H, br-s).

TABLE 179 Ex Data 512 1H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.4 Hz),1.46-1.72 (4H, m), 1.77-1.93 (4H, m), 2.15 (3H, s), 2.20-2.40 (8H, m),2.44-2.63 (8H, m), 2.97-3.08 (2H, m), 3.34-3.46 (2H, m), 3.88-4.00 (2H,m), 4.11 (1H, m), 6.76 (1H, d, J = 7.5 Hz), 6.94 (1H, d, J = 8.6 Hz),7.18 (1H, br-s), 7.34 (1H, m), 7.46 (1H, m), 7.51 (1H, br-s), 11.00 (1H,s). 534 1H-NMR (DMSO-d6): 1.18 (3H, t, J = 7.4 Hz), 1.39-1.61 (4H, m),1.78-1.88 (4H, m), 2.14 (3H, s), 2.20-2.39 (8H, m), 2.44-2.62 (10H, m),2.95-3.06 (4H, m), 3.95 (1H, m), 6.70 (1H, d, J = 7.6 Hz), 6.92 (1H, d,J = 8.6 Hz), 7.15 (1H, br-s), 7.36 (1H, m), 7.43-7.54 (2H, m), 11.01(1H, s). 544 1H-NMR (DMSO-d6): 1.18 (3H, t, J = 7.4 Hz), 1.48-1.72 (4H,m), 1.77-1.90 (4H, m), 1.90-2.01 (2H, m), 2.14 (3H, s), 2.18 (3H, s),2.21-2.62 (16H, m), 2.77-2.87 (2H, m), 2.97-3.07 (2H, m), 3.87 (1H, m),6.72 (1H, m), 6.92 (1H, m), 7.19 (1H, m), 7.28 (1H, m), 7.46-7.56 (2H,m), 11.02 (1H, s) 545 1H-NMR (DMSO-d6): 1.18 (3H, t, J = 7.4 Hz),1.55-1.69 (2H, m), 1.83-1.92 (2H, m), 2.22 (3H, s), 2.40-2.50 (4H, m),2.57 (2H, q, J = 7.4 Hz), 2.98-3.14 (4H, m), 3.36-4.48 (2H, m),3.88-3.98 (2H, m), 4.06 (1H, m), 6.78 (1H, m), 6.84-6.94 (2H, m), 7.18(1H, m), 7.40-7.54 (3H, m), 10.91 (1H, s) 546 1H-NMR (DMSO-d6): 1.18(3H, t, J = 7.4 Hz), 1.42-1.68 (4H, m), 1.78-1.92 (4H, m), 2.13 (3H, s),2.20-2.64 (13H, m), 3.26-3.46 (2H, m), 3.57-3.67 (2H, m), 3.89-3.97 (2H,m), 4.05 (1H, m), 6.78 (1H, m), 6.85-6.93 (2H, m), 7.17 (1H, m),7.42-7.53 (3H, m), 10.89 (1H, s) 547 1H-NMR (DMSO-d6): 1.19 (3H, t, J =7.4 Hz), 1.44-1.72 (4H, m), 1.74-1.90 (4H, m), 2.14 (3H, s), 2.18-2.64(13H, m), 3.18-3.44 (4H, m), 3.81 (3H, s), 3.86-3.96 (2H, m), 4.10 (1H,m), 6.77 (1H, m), 6.82 (1H, m), 7.03 (1H, m), 7.20 (1H, m), 7.25 (1H,m), 7.52 (1H, m), 11.01 (1H, m)

TABLE 180 Ex Data 565 1H-NMR (DMSO-d6): 1.17 (3H, t, J = 7.2 Hz),1.22-1.48 (4H, m), 1.86-1.98 (4H, m), 2.26 (3H, s), 2.47-2.58 (6H, m),3.01-3.14 (4H, m), 3.14-3.60 (1H, m), 3.82-3.87 (1H, m), 4.59 (1H,br-s), 6.60 (1H, s), 6.65 (1H, d, J = 7.6 Hz), 6.83-6.90 (2H, m),7.12-7.19 (1H, m), 7.44-7.54 (3H, m), 10.95 (1H, s) XRD: 12.6, 17.6,22.2, 23.5, 24.2 566 1H-NMR (DMSO-d6): 1.17 (3H, t, J = 7.6 Hz),1.22-1.62 (6H, m), 1.78-2.02 (6H, m), 2.20 (3H, s), 2.24-2.76 (14H, m),3.10-3.88 (4H, m), 6.55 (1H, s), 6.66 (1H, d, J = 6.0 Hz), 6.83-6.90(2H, m), 7.12-7.19 (1H, m), 7.44-7.54 (3H, m), 10.93 (1H, s) XRD: 5.7,18.0, 18.9, 20.1, 20.2 567 1H-NMR (DMSO-d6): 1.13 (6H, d, J = 6.8 Hz),1.21-1.48 (4H, m), 1.84-1.98 (4H, m), 2.26 (3H, s), 2.48-2.56 (4H, m),3.03-3.18 (5H, m), 3.37-3.47 (1H, m), 3.75-3.86 (1H, m), 4.58 (1H,br-s), 6.59 (1H, s), 6.70 (1H, d, J = 7.6 Hz), 6.84-6.90 (2H, m),7.15-7.20 (1H, m), 7.42-7.47 (1H, m), 7.48-7.54 (2H, m), 10.92 (1H, s)XRD: 11.0, 11.2, 17.3, 17.5, 22.5 568 1H-NMR (DMSO-d6): 1.14-1.34 (5H,m), 1.36-1.61 (4H, m), 1.78-1.94 (6H, m), 2.22 (3H, s), 2.28-2.65 (12H,m), 2.68-2.80 (2H, m), 2.89-3.01 (2H, m), 3.36-3.47 (1H, m), 3.81-3.94(1H, m), 6.55 (1H, s), 6.70 (1H, d, J = 7.6 Hz), 7.28-7.32 (1H, m), 7.43(1H, d, J = 8.8 Hz), 7.54-7.64 (2H, m), 8.17 (1H, d, J = 2.4 Hz), 11.39(1H, s) XRD: 8.4, 8.5, 20.2, 20.3, 20.4 569 1H-NMR (DMSO-d6): 1.17 (3H,t, J = 7.6 Hz), 1.21-1.35 (2H, m), 1.36-1.49 (2H, m), 1.50-1.63 (2H, m),1.80-1.98 (6H, m), 2.24 (3H, s), 2.25 (3H, s), 2.30-2.70 (14H, m),2.98-3.10 (2H, m), 3.37-3.48 (1H, m), 3.80-3.92 (1H, m), 6.57 (1H, s),6.65 (1H, d, J = 7.6 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.14-7.22 (1H, m),7.37 (1H, dd, J = 2.4, 8.8 Hz), 7.46-7.53 (2H, m), 11.03 (1H, s) XRD:9.5, 18.4, 19.0, 19.4, 23.9

TABLE 181 Ex Data 570 1H-NMR (DMSO-d6): 1.15 (6H, d, J = 6.4 Hz),1.18-1.32 (2H, m), 1.37-1.58 (4H, m), 1.78-1.91 (6H, m), 2.21 (3H, s),2.28-2.80 (12H, m), 2.89-2.98 (2H, m), 3.10-3.60 (2H, m), 3.82-3.94 (1H,m), 6.55 (1H, s), 6.75 (1H, d, J = 8.0 Hz), 7.28-7.35 (1H, m), 7.43 (1H,d, J = 8.4 Hz), 7.50-7.57 (1H, m), 7.59-7.65 (1H, m), 8.15 (1H, d, J =2.8 Hz), 11.36 (1H, s) XRD: 17.9, 18.3, 18.4, 18.9, 19.0 571 1H-NMR(DMSO-d6): 1.12-1.20 (6H, m), 1.33-1.45 (2H, m), 1.59-1.89 (10H, m),2.23 (3H, s), 2.26 (3H, s), 2.30-2.73 (13H, m), 2.97-3.07 (2H, m),3.79-3.91 (1H, m), 4.03-4.14 (1H, m), 6.57 (1H, s), 6.72 (1H, d, J = 7.6Hz), 6.92 (1H, d, J = 8.4 Hz), 7.14-7.19 (1H, m), 7.28 (1H, dd, J = 2.4,8.4 Hz), 7.46-7.51 (1H, m), 7.56 (1H, d, J = 2.4 Hz), 11.01 (1H, s) XRD:7.9, 15.1, 19.4, 19.9, 20.3 572 1H-NMR (DMSO-d6): 1.04 (6H, d, J = 6.8Hz), 1.17 (3H, t, J = 7.2 Hz), 1.21-1.35 (2H, m), 1.36-1.50 (2H, m),1.84-1.97 (4H, m), 2.27 (3H, s), 2.55 (2H, q, J = 7.2 Hz), 2.62-2.70(4H, m), 2.72-2.86 (5H, m), 3.20-3.55 (2H, m), 3.80-3.91 (1H, m), 6.57(1H, s), 6.66 (1H, d, J = 7.6 Hz), 6.94 (1H, d, J = 8.4 Hz), 7.15-7.21(1H, m), 7.39 (1H, dd, J = 2.4, 8.4 Hz), 7.46-7.52 (2H, m), 11.02 (1H,s) XRD: 10.1, 14.5, 17.9, 22.1, 23.0 573 1H-NMR (DMSO-d6): 1.14-1.22(6H, m), 1.43-1.65 (8H, m), 1.79-1.90 (4H, m), 2.25 (3H, s), 2.27 (3H,s), 2.30-2.70 (14H, m), 2.99-3.09 (2H, m), 3.86-3.98 (1H, m), 6.57 (2H,s), 6.62 (1H, d, J = 7.6 Hz), 6.93 (1H, d, J = 8.4 Hz), 7.15-7.21 (1H,m), 7.36 (1H, dd, J = 2.0, 8.4 Hz), 7.47-7.52 (2H, m), 11.03 (1H, s)XRD: 6.3, 13.7, 16.7, 17.7, 18.4

TABLE 182 Ex Data 574 1H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.6 Hz),1.50-1.72 (4H, m), 1.80-1.93 (4H, m), 2.21 (3H, s), 2.24 (3H, s),2.48-2.65 (13H, m), 2.99-3.08 (2H, m), 3.30-3.50 (2H, m), 3.90-4.00 (2H,m), 4.05-4.18 (1H, m), 6.56 (1H, s), 6.78 (1H, d, J = 7.6 Hz), 6.95 (1H,d, J = 8.4 Hz), 7.17-7.24 (1H, m), 7.34 (1H, dd, J = 2.4, 8.4 Hz), 7.46(1H, d, J = 2.4 Hz), 7.49-7.55 (1H, m), 11.01 (1H, s) XRD: 11.5, 17.7,19.1, 21.4, 22.3 575 1H-NMR (DMSO-d6): 1.17-1.33 (2H, m), 1.43-1.63 (4H,m), 1.79-1.94 (6H, m), 2.25 (3H, s), 2.26 (3H, s), 2.30-2.69 (11H, m),2.99-3.89 (5H, m), 5.75 (2H, s), 6.95 (1H, d, J = 8.4 Hz), 7.07 (1H, d,J = 8.4 Hz), 7.31-7.35 (2H, m), 7.47-7.49 (1H, m), 7.54 (1H, s), 11.19(1H, s) XRD: 5.6, 8.0, 17.8, 18.6, 24.0 576 1H-NMR (DMSO-d6): 1.18 (3H,t, J = 7.2 Hz), 1.44-1.72 (4H, m), 1.80-1.97 (4H, m), 2.21 (3H, s),2.25-2.72 (13H, m), 3.30-3.70 (4H, m), 3.90-3.98 (2H, m), 3.99-4.11 (1H,m), 6.55 (1H, s), 6.78 (1H, d, J = 7.6 Hz), 6.85-6.93 (2H, m), 7.14-7.21(1H, m), 7.43-7.52 (3H, m), 10.89 (1H, s) XRD: 8.9, 16.6, 18.1, 20.1,22.4 577 1H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.6 Hz), 1.49-1.70 (4H, m),1.77-1.91 (4H, m), 2.21 (3H, s), 2.26-2.70 (13H, m), 3.29-3.43 (4H, m),3.81 (3H, s), 3.88-3.97 (2H, m), 4.06-4.18 (1H, m), 6.55 (1H, s), 6.77(1H, d, J = 7.6 Hz), 6.82 (1H, d, J = 8.4 Hz), 7.03 (1H, d, J = 2.0 Hz),7.18-7.29 (2H, m), 7.49-7.55 (1H, m), 11.01 (1H, s) XRD: 11.6, 17.7,19.2, 21.5, 22.4 578 1H-NMR (DMSO-d6): 1.15 (6H, d, J = 6.8 Hz),1.42-1.70 (4H, m), 1.78-1.92 (4H, m), 2.21 (3H, s), 2.26-2.72 (11H, m),3.08-3.21 (1H, m), 3.34-3.48 (2H, m), 3.56-3.69 (2H, m), 3.87-3.98 (2H,m), 4.00-4.13 (1H, m), 6.55 (1H, s), 6.83 (1H, d, J = 7.6 Hz), 6.85-6.93(2H, m), 7.15-7.22 (1H, m), 7.41-7.51 (3H, m), 10.87 (1H, s) XRD: 10.3,16.9, 19.3, 19.9, 21.1

TABLE 183 Ex Data 579 1H-NMR (DMSO-d6): 1.19 (3H, t, J = 7.6 Hz),1.58-1.72 (2H, m), 1.84-1.94 (2H, m), 2.26 (3H, s), 2.45-2.64 (6H, m),2.91-3.02 (4H, m), 3.33-3.49 (2H, m), 3.91-3.99 (2H, m), 4.02-4.14 (1H,m), 6.59 (1H, s), 6.86-6.92 (1H, m), 6.93-7.04 (2H, m), 7.24-7.30 (1H,m), 7.52-7.59 (1H, m), 7.88 (1H, dd, J = 2.4, 16 Hz), 11.18 (1H, s) XRD:5.7, 11.5, 18.2, 23.6, 23.9 580 1H-NMR (DMSO-d6): 1.16 (6H, d, J = 6.8Hz), 1.57-1.70 (2H, m), 1.80-1.89 (2H, m), 2.29 (3H, s), 2.48-2.60 (4H,m), 2.89-3.00 (4H, m), 3.10-3.22 (1H, m), 3.30-3.42 (2H, m), 3.81 (3H,s), 3.87-3.96 (2H, m), 4.06-4.19 (1H, m), 6.58 (1H, s), 6.78-6.86 (2H,m), 7.04 (1H, d, J = 2.0 Hz), 7.19-7.30 (2H, m), 7.46-7.53 (1H, m),11.00 (1H, s) XRD: 8.2, 11.8, 15.9, 18.0, 21.3 581 1H-NMR (DMSO-d6):1.15 (6H, d, J = 6.4 Hz), 1.55-1.70 (2H, m), 1.81-1.91 (2H, m), 2.27(3H, s), 2.47-2.55 (4H, m), 3.01-3.22 (5H, m), 3.34-3.50 (2H, m),3.88-3.98 (2H, m), 4.00-4.13 (1H, m), 6.59 (1H, s), 6.83 (1H, d, J = 7.2Hz), 6.86-6.92 (2H, m), 7.16-7.23 (1H, m), 7.43-7.51 (3H, m), 10.89 (1H,s) XRD: 11.1, 17.2, 19.5, 20.1, 20.5 582 1H-NMR (DMSO-d6): 1.19 (3H, t,J = 7.2 Hz), 1.43-1.57 (2H, m), 1.58-1.71 (2H, m), 1.74-1.91 (4H, m),2.03-2.16 (2H, m), 2.20-2.30 (8H, m), 2.53-2.69 (5H, m), 2.74-2.84 (4H,m), 2.87-2.98 (2H, m), 3.34-3.45 (2H, m), 3.89-3.99 (2H, m), 4.04-4.17(1H, m), 6.52 (1H, s), 6.79 (1H, d, J = 7.6 Hz), 6.96 (1H, d, J = 8.4Hz), 7.18-7.23 (1H, m), 7.36 (1H, dd, J = 2.4, 8.4 Hz), 7.46 (1H, d, J =2.4 Hz), 7.49-7.54 (1H, m), 11.01 (1H, s) XRD: 8.1, 13.1, 15.1, 17.5,23.8

Tables 184 to 201 show the structures of other compounds of the presentinvention. These compounds were synthesized, or can be synthesized,using the above preparation processes, processes described in theExamples, processes obvious to those skilled in the art, or modifiedprocesses thereof.

The meanings of the symbols in the tables are as follows.

No: Compound No.

—R¹¹ and —R¹²: substituents in the general formulas.

cBu: cyclobutyl, 2Py: 2-pyridyl, 3Py: 3-pyridyl, 4Py: 4-pyridyl.

TABLE 184

No —R¹¹ —R¹² A1 —H —H A2 —Me —H A3 —Et —H A4 -nPr —H A5 -iPr —H A6 -cPr—H A7 -cBu —H A8

—H A9

—H A10

—H A11 —CF₃ —H A12 —CN —H A13 —Ph —H A14 —OMe —H A15 —OEt —H A16 —OnPr—H A17 —OiPr —H A18 —OcPr —H A19 —OCH₂cPr —H A20 —OCHCF₂ —H A21 —OCF₃ —HA22 —OCH₂CF₃ —H A23 —OCH₂CH₂F —H A24 —OCH₂CH₂OMe —H A25 —OCH₂CH₂NMe₂ —HA26 —F —H A27 —Cl —H A28 —Br —H A29 —I —H A30a —2Py —H A30b —3Py —H A30c—4Py —H A31 —H —Me A32 —Me —Me A33 —Et —Me A34 -nPr —Me A35 -iPr —Me A36-cPr —Me A37 -cBu —Me A38

—Me A39

—Me A40

—Me A41 —CF₃ —Me A42 —CN —Me A43 —Ph —Me A44 —OMe —Me A45 —OEt —Me A46—OnPr —Me A47 —OiPr —Me A48 —OcPr —Me A49 —OCH₂cPr —Me A50 —OCHCF₂ —MeA51 —OCF₃ —Me A52 —OCH₂CF₃ —Me A53 —OCH₂CH₂F —Me A54 —OCH₂CH₂OMe —Me A55—OCH₂CH₂NMe₂ —Me A56 —F —Me A57 —Cl —Me A58 —Br —Me A59 —I —Me A60a —2Py—Me A60b —3Py —Me A60c —4Py —Me A61 —H —Et A62 —Me —Et A63 —Et —Et A64-nPr —Et A65 -iPr —Et A66 -cPr —Et A67 -cBu —Et A68

—Et A69

—Et A70

—Et A71 —CF₃ —Et A72 —CN —Et A73 —Ph —Et A74 —OMe —Et A75 —OEt —Et A76—OnPr —Et A77 —OiPr —Et A78 —OcPr —Et A79 —OCH₂cPr —Et A80 —OCHCF₂ —EtA81 —OCF₃ —Et A82 —OCH₂CF₃ —Et A83 —OCH₂CH₂F —Et A84 —OCH₂CH₂OMe —Et A85—OCH₂CH₂NMe₂ —Et A86 —F —Et A87 —Cl —Et A88 —Br —Et A89 —I —Et A90a —2Py—Et A90b —3Py —Et A90c —4Py —Et

TABLE 185

No —R¹¹ —R¹² B1 —H -nPr B2 —Me -nPr B3 —Et -nPr B4 -nPr -nPr B5 -iPr-nPr B6 -cPr -nPr B7 -cBu -nPr B8

-nPr B9

-nPr B10

-nPr B11 —CF₃ -nPr B12 —CN -nPr B13 —Ph -nPr B14 —OMe -nPr B15 —OEt -nPrB16 —OnPr -nPr B17 —OiPr -nPr B18 —OcPr -nPr B19 —OCH₂cPr -nPr B20—OCHCF₂ -nPr B21 —OCF₃ -nPr B22 —OCH₂CF₃ -nPr B23 —OCH₂CH₂F -nPr B24—OCH₂CH₂OMe -nPr B25 —OCH₂CH₂NMe₂ -nPr B26 —F -nPr B27 —Cl -nPr B28 —Br-nPr B29 —I -nPr B30a —2Py -nPr B30b —3Py -nPr B30c —4Py -nPr B31 —H-iPr B32 —Me -iPr B33 —Et -iPr B34 -nPr -iPr B35 -iPr -iPr B36 -cPr -iPrB37 -cBu -iPr B38

-iPr B39

-iPr B40

-iPr B41 —CF₃ -iPr B42 —CN -iPr B43 —Ph -iPr B44 —OMe -iPr B45 —OEt -iPrB46 —OnPr -iPr B47 —OiPr -iPr B48 —OcPr -iPr B49 —OCH₂cPr -iPr B50—OCHCF₂ -iPr B51 —OCF₃ -iPr B52 —OCH₂CF₃ -iPr B53 —OCH₂CH₂F -iPr B54—OCH₂CH₂OMe -iPr B55 —OCH₂CH₂NMe₂ -iPr B56 —F -iPr B57 —Cl -iPr B58 —Br-iPr B59 —I -iPr B60a —2Py -iPr B60b —3Py -iPr B60c —4Py -iPr B61 —H-cPr B62 —Me -cPr B63 —Et -cPr B64 -nPr -cPr B65 -iPr -cPr B66 -cPr -cPrB67 -cBu -cPr B68

-cPr B69

-cPr B70

-cPr B71 —CF₃ -cPr B72 —CN -cPr B73 —Ph -cPr B74 —OMe -cPr B75 —OEt -cPrB76 —OnPr -cPr B77 —OiPr -cPr B78 —OcPr -cPr B79 —OCH₂cPr -cPr B80—OCHCF₂ -cPr B81 —OCF₃ -cPr B82 —OCH₂CF₃ -cPr B83 —OCH₂CH₂F -cPr B84—OCH₂CH₂OMe -cPr B85 —OCH₂CH₂NMe₂ -cPr B86 —F -cPr B87 —Cl -cPr B88 —Br-cPr B89 —I -cPr B90a —2Py -cPr B90b —3Py -cPr B90c —4Py -cPr

TABLE 186

No —R¹¹ —R¹² C1 —H —Cl C2 —Me —Cl C3 —Et —Cl C4 -nPr —Cl C5 -iPr —Cl C6-cPr —Cl C7 -cBu —Cl C8

—Cl C9

—Cl C10

—Cl C11 —CF₃ —Cl C12 —CN —Cl C13 —Ph —Cl C14 —OMe —Cl C15 —OEt —Cl C16—OnPr —Cl C17 —OiPr —Cl C18 —OcPr —Cl C19 —OCH₂cPr —Cl C20 —OCHCF₂ —ClC21 —OCF₃ —Cl C22 —OCH₂CF₃ —Cl C23 —OCH₂CH₂F —Cl C24 —OCH₂CH₂OMe —Cl C25—OCH₂CH₂NMe₂ —Cl C26 —F —Cl C27 —Cl —Cl C28 —Br —Cl C29 —I —Cl C30a —2Py—Cl C30b —3Py —Cl C30c —4Py —Cl C31 —H —Br C32 —Me —Br C33 —Et —Br C34-nPr —Br C35 -iPr —Br C36 -cPr —Br C37 -cBu —Br C38

—Br C39

—Br C40

—Br C41 —CF₃ —Br C42 —CN —Br C43 —Ph —Br C44 —OMe —Br C45 —OEt —Br C46—OnPr —Br C47 —OiPr —Br C48 —OcPr —Br C49 —OCH₂cPr —Br C50 —OCHCF₂ —BrC51 —OCF₃ —Br C52 —OCH₂CF₃ —Br C53 —OCH₂CH₂F —Br C54 —OCH₂CH₂OMe —Br C55—OCH₂CH₂NMe₂ —Br C56 —F —Br C57 —Cl —Br C58 —Br —Br C59 —I —Br C60a —2Py—Br C60b —3Py —Br C60c —4Py —Br C61 —H —I C62 —Me —I C63 —Et —I C64 -nPr—I C65 -iPr —I C66 -cPr —I C67 -cBu —I C68

—I C69

—I C70

—I C71 —CF₃ —I C72 —CN —I C73 —Ph —I C74 —OMe —I C75 —OEt —I C76 —OnPr—I C77 —OiPr —I C78 —OcPr —I C79 —OCH₂cPr —I C80 —OCHCF₂ —I C81 —OCF₃ —IC82 —OCH₂CF₃ —I C83 —OCH₂CH₂F —I C84 —OCH₂CH₂OMe —I C85 —OCH₂CH₂NMe₂ —IC86 —F —I C87 —Cl —I C88 —Br —I C89 —I —I C90a —2Py —I C90b —3Py —I C90c—4Py —I

TABLE 187

No —R¹¹ —R¹² D1 —H —H D2 —Me —H D3 —Et —H D4 -nPr —H D5 -iPr —H D6 -cPr—H D7 -cBu —H D8

—H D9

—H D10

—H D11 —CF₃ —H D12 —CN —H D13 —Ph —H D14 —OMe —H D15 —OEt —H D16 —OnPr—H D17 —OiPr —H D18 —OcPr —H D19 —OCH₂cPr —H D20 —OCHCF₂ —H D21 —OCF₃ —HD22 —OCH₂CF₃ —H D23 —OCH₂CH₂F —H D24 —OCH₂CH₂OMe —H D25 —OCH₂CH₂NMe₂ —HD26 —F —H D27 —Cl —H D28 —Br —H D29 —I —H D30a —2Py —H D30b —3Py —H D30c—4Py —H D31 —H —Me D32 —Me —Me D33 —Et —Me D34 -nPr —Me D35 -iPr —Me D36-cPr —Me D37 -cBu —Me D38

—Me D39

—Me D40

—Me D41 —CF₃ —Me D42 —CN —Me D43 —Ph —Me D44 —OMe —Me D45 —OEt —Me D46—OnPr —Me D47 —OiPr —Me D48 —OcPr —Me D49 —OCH₂cPr —Me D50 —OCHCF₂ —MeD51 —OCF₃ —Me D52 —OCH₂CF₃ —Me D53 —OCH₂CH₂F —Me D54 —OCH₂CH₂OMe —Me D55—OCH₂CH₂NMe₂ —Me D56 —F —Me D57 —Cl —Me D58 —Br —Me D59 —I —Me D60a —2Py—Me D60b —3Py —Me D60c —4Py —Me D61 —H —Et D62 —Me —Et D63 —Et —Et D64-nPr —Et D65 -iPr —Et D66 -cPr —Et D67 -cBu —Et D68

—Et D69

—Et D70

—Et D71 —CF₃ —Et D72 —CN —Et D73 —Ph —Et D74 —OMe —Et D75 —OEt —Et D76—OnPr —Et D77 —OiPr —Et D78 —OcPr —Et D79 —OCH₂cPr —Et D80 —OCHCF₂ —EtD81 —OCF₃ —Et D82 —OCH₂CF₃ —Et D83 —OCH₂CH₂F —Et D84 —OCH₂CH₂OMe —Et D85—OCH₂CH₂NMe₂ —Et D86 —F —Et D87 —Cl —Et D88 —Br —Et D89 —I —Et D90a —2Py—Et D90b —3Py —Et D90c —4Py —Et

TABLE 188

No —R¹¹ —R¹² E1 —H -nPr E2 —Me -nPr E3 —Et -nPr E4 -nPr -nPr E5 -iPr-nPr E6 -cPr -nPr E7 -cBu -nPr E8

-nPr E9

-nPr E10

-nPr E11 —CF₃ -nPr E12 —CN -nPr E13 —Ph -nPr E14 —OMe -nPr E15 —OEt -nPrE16 —OnPr -nPr E17 —OiPr -nPr E18 —OcPr -nPr E19 —OCH₂cPr -nPr E20—OCHCF₂ -nPr E21 —OCF₃ -nPr E22 —OCH₂CF₃ -nPr E23 —OCH₂CH₂F -nPr E24—OCH₂CH₂OMe -nPr E25 —OCH₂CH₂NMe₂ -nPr E26 —F -nPr E27 —Cl -nPr E28 —Br-nPr E29 —I -nPr E30a —2Py -nPr E30b —3Py -nPr E30c —4Py -nPr E31 —H-iPr E32 —Me -iPr E33 —Et -iPr E34 -nPr -iPr E35 -iPr -iPr E36 -cPr -iPrE37 -cBu -iPr E38

-iPr E39

-iPr E40

-iPr E41 —CF₃ -iPr E42 —CN -iPr E43 —Ph -iPr E44 —OMe -iPr E45 —OEt -iPrE46 —OnPr -iPr E47 —OiPr -iPr E48 —OcPr -iPr E49 —OCH₂cPr -iPr E50—OCHCF₂ -iPr E51 —OCF₃ -iPr E52 —OCH₂CF₃ -iPr E53 —OCH₂CH₂F -iPr E54—OCH₂CH₂OMe -iPr E55 —OCH₂CH₂NMe₂ -iPr E56 —F -iPr E57 —Cl -iPr E58 —Br-iPr E59 —I -iPr E60a —2Py -iPr E60b —3Py -iPr E60c —4Py -iPr E61 —H-cPr E62 —Me -cPr E63 —Et -cPr E64 -nPr -cPr E65 -iPr -cPr E66 -cPr -cPrE67 -cBu -cPr E68

-cPr E69

-cPr E70

-cPr E71 —CF₃ -cPr E72 —CN -cPr E73 —Ph -cPr E74 —OMe -cPr E75 —OEt -cPrE76 —OnPr -cPr E77 —OiPr -cPr E78 —OcPr -cPr E79 —OCH₂cPr -cPr E80—OCHCF₂ -cPr E81 —OCF₃ -cPr E82 —OCH₂CF₃ -cPr E83 —OCH₂CH₂F -cPr E84—OCH₂CH₂OMe -cPr E85 —OCH₂CH₂NMe₂ -cPr E86 —F -cPr E87 —Cl -cPr E88 —Br-cPr E89 —I -cPr E90a —2Py -cPr E90b —3Py -cPr E90c —4Py -cPr

TABLE 189

No —R¹¹ —R¹² F1 —H —Cl F2 —Me —Cl F3 —Et —Cl F4 -nPr —Cl F5 -iPr —Cl F6-cPr —Cl F7 -cBu —Cl F8

—Cl F9

—Cl F10

—Cl F11 —CF₃ —Cl F12 —CN —Cl F13 —Ph —Cl F14 —OMe —Cl F15 —OEt —Cl F16—OnPr —Cl F17 —OiPr —Cl F18 —OcPr —Cl F19 —OCH₂cPr —Cl F20 —OCHCF₂ —ClF21 —OCF₃ —Cl F22 —OCH₂CF₃ —Cl F23 —OCH₂CH₂F —Cl F24 —OCH₂CH₂OMe —Cl F25—OCH₂CH₂NMe₂ —Cl F26 —F —Cl F27 —Cl —Cl F28 —Br —Cl F29 —I —Cl F30a —2Py—Cl F30b —3Py —Cl F30c —4Py —Cl F31 —H —Br F32 —Me —Br F33 —Et —Br F34-nPr —Br F35 -iPr —Br F36 -cPr —Br F37 -cBu —Br F38

—Br F39

—Br F40

—Br F41 —CF₃ —Br F42 —CN —Br F43 —Ph —Br F44 —OMe —Br F45 —OEt —Br F46—OnPr —Br F47 —OiPr —Br F48 —OcPr —Br F49 —OCH₂cPr —Br F50 —OCHCF₂ —BrF51 —OCF₃ —Br F52 —OCH₂CF₃ —Br F53 —OCH₂CH₂F —Br F54 —OCH₂CH₂OMe —Br F55—OCH₂CH₂NMe₂ —Br F56 —F —Br F57 —Cl —Br F58 —Br —Br F59 —I —Br F60a —2Py—Br F60b —3Py —Br F60c —4Py —Br F61 —H —I F62 —Me —I F63 —Et —I F64 -nPr—I F65 -iPr —I F66 -cPr —I F67 -cBu —I F68

—I F69

—I F70

—I F71 —CF₃ —I F72 —CN —I F73 —Ph —I F74 —OMe —I F75 —OEt —I F76 —OnPr—I F77 —OiPr —I F78 —OcPr —I F79 —OCH₂cPr —I F80 —OCHCF₂ —I F81 —OCF₃ —IF82 —OCH₂CF₃ —I F83 —OCH₂CH₂F —I F84 —OCH₂CH₂OMe —I F85 —OCH₂CH₂NMe₂ —IF86 —F —I F87 —Cl —I F88 —Br —I F89 —I —I F90a —2Py —I F90b —3Py —I F90c—4Py —I

TABLE 190

No —R¹¹ —R¹² G1 —H —H G2 —Me —H G3 —Et —H G4 -nPr —H G5 -iPr —H G6 -cPr—H G7 -cBu —H G8

—H G9

—H G10

—H G11 —CF₃ —H G12 —CN —H G13 —Ph —H G14 —OMe —H G15 —OEt —H G16 —OnPr—H G17 —OiPr —H G18 —OcPr —H G19 —OCH₂cPr —H G20 —OCHCF₂ —H G21 —OCF₃ —HG22 —OCH₂CF₃ —H G23 —OCH₂CH₂F —H G24 —OCH₂CH₂OMe —H G25 —OCH₂CH₂NMe₂ —HG26 —F —H G27 —Cl —H G28 —Br —H G29 —I —H G30a —2Py —H G30b —3Py —H G30c—4Py —H G31 —H —Me G32 —Me —Me G33 —Et —Me G34 -nPr —Me G35 -iPr —Me G36-cPr —Me G37 -cBu —Me G38

—Me G39

—Me G40

—Me G41 —CF₃ —Me G42 —CN —Me G43 —Ph —Me G44 —OMe —Me G45 —OEt —Me G46—OnPr —Me G47 —OiPr —Me G48 —OcPr —Me G49 —OCH₂cPr —Me G50 —OCHCF₂ —MeG51 —OCF₃ —Me G52 —OCH₂CF₃ —Me G53 —OCH₂CH₂F —Me G54 —OCH₂CH₂OMe —Me G55—OCH₂CH₂NMe₂ —Me G56 —F —Me G57 —Cl —Me G58 —Br —Me G59 —I —Me G60a —2Py—Me G60b —3Py —Me G60c —4Py —Me G61 —H —Et G62 —Me —Et G63 —Et —Et G64-nPr —Et G65 -iPr —Et G66 -cPr —Et G67 -cBu —Et G68

—Et G69

—Et G70

—Et G71 —CF₃ —Et G72 —CN —Et G73 —Ph —Et G74 —OMe —Et G75 —OEt —Et G76—OnPr —Et G77 —OiPr —Et G78 —OcPr —Et G79 —OCH₂cPr —Et G80 —OCHCF₂ —EtG81 —OCF₃ —Et G82 —OCH₂CF₃ —Et G83 —OCH₂CH₂F —Et G84 —OCH₂CH₂OMe —Et G85—OCH₂CH₂NMe₂ —Et G86 —F —Et G87 —Cl —Et G88 —Br —Et G89 —I —Et G90a —2Py—Et G90b —3Py —Et G90c —4Py —Et

TABLE 191

No —R¹¹ —R¹² H1 —H -nPr H2 —Me -nPr H3 —Et -nPr H4 -nPr -nPr H5 -iPr-nPr H6 -cPr -nPr H7 -cBu -nPr H8

-nPr H9

-nPr H10

-nPr H11 —CF₃ -nPr H12 —CN -nPr H13 —Ph -nPr H14 —OMe -nPr H15 —OEt -nPrH16 —OnPr -nPr H17 —OiPr -nPr H18 —OcPr -nPr H19 —OCH₂cPr -nPr H20—OCHCF₂ -nPr H21 —OCF₃ -nPr H22 —OCH₂CF₃ -nPr H23 —OCH₂CH₂F -nPr H24—OCH₂CH₂OMe -nPr H25 —OCH₂CH₂NMe₂ -nPr H26 —F -nPr H27 —Cl -nPr H28 —Br-nPr H29 —I -nPr H30a —2Py -nPr H30b —3Py -nPr H30c —4Py -nPr H31 —H-iPr H32 —Me -iPr H33 —Et -iPr H34 -nPr -iPr H35 -iPr -iPr H36 -cPr -iPrH37 -cBu -iPr H38

-iPr H39

-iPr H40

-iPr H41 —CF₃ -iPr H42 —CN -iPr H43 —Ph -iPr H44 —OMe -iPr H45 —OEt -iPrH46 —OnPr -iPr H47 —OiPr -iPr H48 —OcPr -iPr H49 —OCH₂cPr -iPr H50—OCHCF₂ -iPr H51 —OCF₃ -iPr H52 —OCH₂CF₃ -iPr H53 —OCH₂CH₂F -iPr H54—OCH₂CH₂OMe -iPr H55 —OCH₂CH₂NMe₂ -iPr H56 —F -iPr H57 —Cl -iPr H58 —Br-iPr H59 —I -iPr H60a —2Py -iPr H60b —3Py -iPr H60c —4Py -iPr H61 —H-cPr H62 —Me -cPr H63 —Et -cPr H64 -nPr -cPr H65 -iPr -cPr H66 -cPr -cPrH67 -cBu -cPr H68

-cPr H69

-cPr H70

-cPr H71 —CF₃ -cPr H72 —CN -cPr H73 —Ph -cPr H74 —OMe -cPr H75 —OEt -cPrH76 —OnPr -cPr H77 —OiPr -cPr H78 —OcPr -cPr H79 —OCH₂cPr -cPr H80—OCHCF₂ -cPr H81 —OCF₃ -cPr H82 —OCH₂CF₃ -cPr H83 —OCH₂CH₂F -cPr H84—OCH₂CH₂OMe -cPr H85 —OCH₂CH₂NMe₂ -cPr H86 —F -cPr H87 —Cl -cPr H88 —Br-cPr H89 —I -cPr H90a —2Py -cPr H90b —3Py -cPr H90c —4Py -cPr

TABLE 192

No —R¹¹ —R¹² I1 —H —Cl I2 —Me —Cl I3 —Et —Cl I4 -nPr —Cl I5 -iPr —Cl I6-cPr —Cl I7 -cBu —Cl I8

—Cl I9

—Cl I10

—Cl I11 —CF₃ —Cl I12 —CN —Cl I13 —Ph —Cl I14 —OMe —Cl I15 —OEt —Cl I16—OnPr —Cl I17 —OiPr —Cl I18 —OcPr —Cl I19 —OCH₂cPr —Cl I20 —OCHCF₂ —ClI21 —OCF₃ —Cl I22 —OCH₂CF₃ —Cl I23 —OCH₂CH₂F —Cl I24 —OCH₂CH₂OMe —Cl I25—OCH₂CH₂NMe₂ —Cl I26 —F —Cl I27 —Cl —Cl I28 —Br —Cl I29 —I —Cl I30a —2Py—Cl I30b —3Py —Cl I30c —4Py —Cl I31 —H —Br I32 —Me —Br I33 —Et —Br I34-nPr —Br I35 -iPr —Br I36 -cPr —Br I37 -cBu —Br I38

—Br I39

—Br I40

—Br I41 —CF₃ —Br I42 —CN —Br I43 —Ph —Br I44 —OMe —Br I45 —OEt —Br I46—OnPr —Br I47 —OiPr —Br I48 —OcPr —Br I49 —OCH₂cPr —Br I50 —OCHCF₂ —BrI51 —OCF₃ —Br I52 —OCH₂CF₃ —Br I53 —OCH₂CH₂F —Br I54 —OCH₂CH₂OMe —Br I55—OCH₂CH₂NMe₂ —Br I56 —F —Br I57 —Cl —Br I58 —Br —Br I59 —I —Br I60a —2Py—Br I60b —3Py —Br I60c —4Py —Br I61 —H —I I62 —Me —I I63 —Et —I I64 -nPr—I I65 -iPr —I I66 -cPr —I I67 -cBu —I I68

—I I69

—I I70

—I I71 —CF₃ —I I72 —CN —I I73 —Ph —I I74 —OMe —I I75 —OEt —I I76 —OnPr—I I77 —OiPr —I I78 —OcPr —I I79 —OCH₂cPr —I I80 —OCHCF₂ —I I81 —OCF₃ —II82 —OCH₂CF₃ —I I83 —OCH₂CH₂F —I I84 —OCH₂CH₂OMe —I I85 —OCH₂CH₂NMe₂ —II86 —F —I I87 —Cl —I I88 —Br —I I89 —I —I I90a —2Py —I I90b —3Py —I I90c—4Py —I

TABLE 193

No —R¹¹ —R¹² J1 —H —H J2 —Me —H J3 —Et —H J4 -nPr —H J5 -iPr —H J6 -cPr—H J7 -cBu —H J8

—H J9

—H J10

—H J11 —CF₃ —H J12 —CN —H J13 —Ph —H J14 —OMe —H J15 —OEt —H J16 —OnPr—H J17 —OiPr —H J18 —OcPr —H J19 —OCH₂cPr —H J20 —OCHCF₂ —H J21 —OCF₃ —HJ22 —OCH₂CF₃ —H J23 —OCH₂CH₂F —H J24 —OCH₂CH₂OMe —H J25 —OCH₂CH₂NMe₂ —HJ26 —F —H J27 —Cl —H J28 —Br —H J29 —I —H J30a —2Py —H J30b —3Py —H J30c—4Py —H J31 —H —Me J32 —Me —Me J33 —Et —Me J34 -nPr —Me J35 -iPr —Me J36-cPr —Me J37 -cBu —Me J38

—Me J39

—Me J40

—Me J41 —CF₃ —Me J42 —CN —Me J43 —Ph —Me J44 —OMe —Me J45 —OEt —Me J46—OnPr —Me J47 —OiPr —Me J48 —OcPr —Me J49 —OCH₂cPr —Me J50 —OCHCF₂ —MeJ51 —OCF₃ —Me J52 —OCH₂CF₃ —Me J53 —OCH₂CH₂F —Me J54 —OCH₂CH₂OMe —Me J55—OCH₂CH₂NMe₂ —Me J56 —F —Me J57 —Cl —Me J58 —Br —Me J59 —I —Me J60a —2Py—Me J60b —3Py —Me J60c —4Py —Me J61 —H —Et J62 —Me —Et J63 —Et —Et J64-nPr —Et J65 -iPr —Et J66 -cPr —Et J67 -cBu —Et J68

—Et J69

—Et J70

—Et J71 —CF₃ —Et J72 —CN —Et J73 —Ph —Et J74 —OMe —Et J75 —OEt —Et J76—OnPr —Et J77 —OiPr —Et J78 —OcPr —Et J79 —OCH₂cPr —Et J80 —OCHCF₂ —EtJ81 —OCF₃ —Et J82 —OCH₂CF₃ —Et J83 —OCH₂CH₂F —Et J84 —OCH₂CH₂OMe —Et J85—OCH₂CH₂NMe₂ —Et J86 —F —Et J87 —Cl —Et J88 —Br —Et J89 —I —Et J90a —2Py—Et J90b —3Py —Et J90c —4Py —Et

TABLE 194

No —R¹¹ —R¹² K1 —H -nPr K2 —Me -nPr K3 —Et -nPr K4 -nPr -nPr K5 -iPr-nPr K6 -cPr -nPr K7 -cBu -nPr K8

-nPr K9

-nPr K10

-nPr K11 —CF₃ -nPr K12 —CN -nPr K13 —Ph -nPr K14 —OMe -nPr K15 —OEt -nPrK16 —OnPr -nPr K17 —OiPr -nPr K18 —OcPr -nPr K19 —OCH₂cPr -nPr K20—OCHCF₂ -nPr K21 —OCF₃ -nPr K22 —OCH₂CF₃ -nPr K23 —OCH₂CH₂F -nPr K24—OCH₂CH₂OMe -nPr K25 —OCH₂CH₂NMe₂ -nPr K26 —F -nPr K27 —Cl -nPr K28 —Br-nPr K29 —I -nPr K30a —2Py -nPr K30b —3Py -nPr K30c —4Py -nPr K31 —H-iPr K32 —Me -iPr K33 —Et -iPr K34 -nPr -iPr K35 -iPr -iPr K36 -cPr -iPrK37 -cBu -iPr K38

-iPr K39

-iPr K40

-iPr K41 —CF₃ -iPr K42 —CN -iPr K43 —Ph -iPr K44 —OMe -iPr K45 —OEt -iPrK46 —OnPr -iPr K47 —OiPr -iPr K48 —OcPr -iPr K49 —OCH₂cPr -iPr K50—OCHCF₂ -iPr K51 —OCF₃ -iPr K52 —OCH₂CF₃ -iPr K53 —OCH₂CH₂F -iPr K54—OCH₂CH₂OMe -iPr K55 —OCH₂CH₂NMe₂ -iPr K56 —F -iPr K57 —Cl -iPr K58 —Br-iPr K59 —I -iPr K60a —2Py -iPr K60b —3Py -iPr K60c —4Py -iPr K61 —H-cPr K62 —Me -cPr K63 —Et -cPr K64 -nPr -cPr K65 -iPr -cPr K66 -cPr -cPrK67 -cBu -cPr K68

-cPr K69

-cPr K70

-cPr K71 —CF₃ -cPr K72 —CN -cPr K73 —Ph -cPr K74 —OMe -cPr K75 —OEt -cPrK76 —OnPr -cPr K77 —OiPr -cPr K78 —OcPr -cPr K79 —OCH₂cPr -cPr K80—OCHCF₂ -cPr K81 —OCF₃ -cPr K82 —OCH₂CF₃ -cPr K83 —OCH₂CH₂F -cPr K84—OCH₂CH₂OMe -cPr K85 —OCH₂CH₂NMe₂ -cPr K86 —F -cPr K87 —Cl -cPr K88 —Br-cPr K89 —I -cPr K90a —2Py -cPr K90b —3Py -cPr K90c —4Py -cPr

TABLE 195

No —R¹¹ —R¹² L1 —H —Cl L2 —Me —Cl L3 —Et —Cl L4 -nPr —Cl L5 -iPr —Cl L6-cPr —Cl L7 -cBu —Cl L8

—Cl L9

—Cl L10

—Cl L11 —CF₃ —Cl L12 —CN —Cl L13 —Ph —Cl L14 —OMe —Cl L15 —OEt —Cl L16—OnPr —Cl L17 —OiPr —Cl L18 —OcPr —Cl L19 —OCH₂cPr —Cl L20 —OCHCF₂ —ClL21 —OCF₃ —Cl L22 —OCH₂CF₃ —Cl L23 —OCH₂CH₂F —Cl L24 —OCH₂CH₂OMe —Cl L25—OCH₂CH₂NMe₂ —Cl L26 —F —Cl L27 —Cl —Cl L28 —Br —Cl L29 —I —Cl L30a —2Py—Cl L30b —3Py —Cl L30c —4Py —Cl L31 —H —Br L32 —Me —Br L33 —Et —Br L34-nPr —Br L35 -iPr —Br L36 -cPr —Br L37 -cBu —Br L38

—Br L39

—Br L40

—Br L41 —CF₃ —Br L42 —CN —Br L43 —Ph —Br L44 —OMe —Br L45 —OEt —Br L46—OnPr —Br L47 —OiPr —Br L48 —OcPr —Br L49 —OCH₂cPr —Br L50 —OCHCF₂ —BrL51 —OCF₃ —Br L52 —OCH₂CF₃ —Br L53 —OCH₂CH₂F —Br L54 —OCH₂CH₂OMe —Br L55—OCH₂CH₂NMe₂ —Br L56 —F —Br L57 —Cl —Br L58 —Br —Br L59 —I —Br L60a —2Py—Br L60b —3Py —Br L60c —4Py —Br L61 —H —I L62 —Me —I L63 —Et —I L64 -nPr—I L65 -iPr —I L66 -cPr —I L67 -cBu —I L68

—I L69

—I L70

—I L71 —CF₃ —I L72 —CN —I L73 —Ph —I L74 —OMe —I L75 —OEt —I L76 —OnPr—I L77 —OiPr —I L78 —OcPr —I L79 —OCH₂cPr —I L80 —OCHCF₂ —I L81 —OCF₃ —IL82 —OCH₂CF₃ —I L83 —OCH₂CH₂F —I L84 —OCH₂CH₂OMe —I L85 —OCH₂CH₂NMe₂ —IL86 —F —I L87 —Cl —I L88 —Br —I L89 —I —I L90a —2Py —I L90b —3Py —I L90c—4Py —I

TABLE 196

No —R¹¹ —R¹² M1 —H —H M2 —Me —H M3 —Et —H M4 -nPr —H M5 -iPr —H M5 -cPr—H M7 -cBu —H M8

—H M9

—H M10

—H M11 —CF₃ —H M12 —CN —H M13 —Ph —H M14 —OMe —H M15 —OEt —H M16 —OnPr—H M17 —OiPr —H M18 —OcPr —H M19 —OCH₂cPr —H M20 —OCHCF₂ —H M21 —OCF₃ —HM22 —OCH₂CF₃ —H M23 —OCH₂CH₂F —H M24 —OCH₂CH₂OMe —H M25 —OCH₂CH₂NMe₂ —HM26 —F —H M27 —Cl —H M28 —Br —H M29 —I —H M30a —2Py —H M30b —3Py —H M30c—4Py —H M31 —H —Me M32 —Me —Me M33 —Et —Me M34 -nPr —Me M35 -iPr —Me M36-cPr —Me M37 -cBu —Me M38

—Me M39

—Me M40

—Me M41 —CF₃ —Me M42 —CN —Me M43 —Ph —Me M44 —OMe —Me M45 —OEt —Me M46—OnPr —Me M47 —OiPr —Me M48 —OcPr —Me M49 —OCH₂cPr —Me M50 —OCHCF₂ —MeM51 —OCF₃ —Me M52 —OCH₂CF₃ —Me M53 —OCH₂CH₂F —Me M54 —OCH₂CH₂OMe —Me M55—OCH₂CH₂NMe₂ —Me M56 —F —Me M57 —Cl —Me M58 —Br —Me M59 —I —Me M60a —2Py—Me M60b —3Py —Me M60c —4Py —Me M61 —H —Et M62 —Me —Et M63 —Et —Et M64-nPr —Et M65 -iPr —Et M66 -cPr —Et M67 -cBu —Et M68

—Et M69

—Et M70

—Et M71 —CF₃ —Et M72 —CN —Et M73 —Ph —Et M74 —OMe —Et M75 —OEt —Et M76—OnPr —Et M77 —OiPr —Et M78 —OcPr —Et M79 —OCH₂cPr —Et M80 —OCHCF₂ —EtM81 —OCF₃ —Et M82 —OCH₂CF₃ —Et M83 —OCH₂CH₂F —Et M84 —OCH₂CH₂OMe —Et M85—OCH₂CH₂NMe₂ —Et M86 —F —Et M87 —Cl —Et M88 —Br —Et M89 —I —Et M90a —2Py—Et M90b —3Py —Et M90c —4Py —Et

TABLE 197

No —R¹¹ —R¹² N1 —H -nPr N2 —Me -nPr N3 —Et -nPr N4 -nPr -nPr N5 -iPr-nPr N6 -cPr -nPr N7 -cBu -nPr N8

-nPr N9

-nPr N10

-nPr N11 —CF₃ -nPr N12 —CN -nPr N13 —Ph -nPr N14 —OMe -nPr N15 —OEt -nPrN16 —OnPr -nPr N17 —OiPr -nPr N18 —OcPr -nPr N19 —OCH₂cPr -nPr N20—OCHCF₂ -nPr N21 —OCF₃ -nPr N22 —OCH₂CF₃ -nPr N23 —OCH₂CH₂F -nPr N24—OCH₂CH₂OMe -nPr N25 —OCH₂CH₂NMe₂ -nPr N26 —F -nPr N27 —Cl -nPr N28 —Br-nPr N29 —I -nPr N30a —2Py -nPr N30b —3Py -nPr N30c —4Py -nPr N31 —H-iPr N32 —Me -iPr N33 —Et -iPr N34 -nPr -iPr N35 -iPr -iPr N36 -cPr -iPrN37 -cBu -iPr N38

-iPr N39

-iPr N40

—iPr N41 —CF₃ -iPr N42 —CN -iPr N43 —Ph -iPr N44 —OMe -iPr N45 —OEt -iPrN46 —OnPr -iPr N47 —OiPr -iPr N48 —OcPr -iPr N49 —OCH₂cPr -iPr N50—OCHCF₂ -iPr N51 —OCF₃ -iPr N52 —OCH₂CF₃ -iPr N53 —OCH₂CH₂F -iPr N54—OCH₂CH₂OMe -iPr N55 —OCH₂CH₂NMe₂ -iPr N56 —F -iPr N57 —Cl -iPr N58 —Br-iPr N59 —I -iPr N60a —2Py -iPr N60b —3Py -iPr N60c —4Py -iPr N61 —H-cPr N62 —Me -cPr N63 —Et -cPr N64 -nPr -cPr N65 -iPr -cPr N66 -cPr -cPrN67 -cBu -cPr N68

-cPr N69

-cPr N70

-cPr N71 —CF₃ -cPr N72 —CN -cPr N73 —Ph -cPr N74 —OMe -cPr N75 —OEt -cPrN76 —OnPr -cPr N77 —OiPr -cPr N78 —OcPr -cPr N79 —OCH₂cPr -cPr N80—OCHCF₂ -cPr N81 —OCF₃ -cPr N82 —OCH₂CF₃ -cPr N83 —OCH₂CH₂F -cPr N84—OCH₂CH₂OMe -cPr N85 —OCH₂CH₂NMe₂ -cPr N86 —F -cPr N87 —Cl -cPr N88 —Br-cPr N89 —I -cPr N90a —2Py -cPr N90b —3Py -cPr N90c —4Py -cPr

TABLE 198

No —R¹¹ —R¹² O1 —H —Cl O2 —Me —Cl O3 —Et —Cl O4 -nPr —Cl O5 -iPr —Cl O6-cPr —Cl O7 -cBu —Cl O8

—Cl O9

—Cl O10

—Cl O11 —CF₃ —Cl O12 —CN —Cl O13 —Ph —Cl O14 —OMe —Cl O15 —OEt —Cl O16—OnPr —Cl O17 —OiPr —Cl O18 —OcPr —Cl O19 —OCH₂cPr —Cl O20 —OCHCF₂ —ClO21 —OCF₃ —Cl O22 —OCH₂CF₃ —Cl O23 —OCH₂CH₂F —Cl O24 —OCH₂CH₂OMe —Cl O25—OCH₂CH₂NMe₂ —Cl O26 —F —Cl O27 —Cl —Cl O28 —Br —Cl O29 —I —Cl O30a —2Py—Cl O30b —3Py —Cl O30c —4Py —Cl O31 —H —Br O32 —Me —Br O33 —Et —Br O34-nPr —Br O35 -iPr —Br O36 -cPr —Br O37 -cBu —Br O38

—Br O39

—Br O40

—Br O41 —CF₃ —Br O42 —CN —Br O43 —Ph —Br O44 —OMe —Br O45 —OEt —Br O46—OnPr —Br O47 —OiPr —Br O48 —OcPr —Br O49 —OCH₂cPr —Br O50 —OCHCF₂ —BrO51 —OCF₃ —Br O52 —OCH₂CF₃ —Br O53 —OCH₂CH₂F —Br O54 —OCH₂CH₂OMe —Br O55—OCH₂CH₂NMe₂ —Br O56 —F —Br O57 —Cl —Br O58 —Br —Br O59 —I —Br O60a —2Py—Br O60b —3Py —Br O60c —4Py —Br O61 —H —I O62 —Me —I O63 —Et —I O64 -nPr—I O65 -iPr —I O66 -cPr —I O67 -cBu —I O68

—I O69

—I O70

—I O71 —CF₃ —I O72 —CN —I O73 —Ph —I O74 —OMe —I O75 —OEt —I O76 —OnPr—I O77 —OiPr —I O78 —OcPr —I O79 —OCH₂cPr —I O80 —OCHCF₂ —I O81 —OCF₃ —IO82 —OCH₂CF₃ —I O83 —OCH₂CH₂F —I O84 —OCH₂CH₂OMe —I O85 —OCH₂CH₂NMe₂ —IO86 —F —I O87 —Cl —I O88 —Br —I O89 —I —I O90a —2Py —I O90b —3Py —I O90c—4Py —I

TABLE 199

No —R¹¹ —R¹² P1 —H —H P2 —Me —H P3 —Et —H P4 -nPr —H P5 -iPr —H P6 -cPr—H P7 -cBu —H P8

—H P9

—H P10

—H P11 —CF₃ —H P12 —CN —H P13 —Ph —H P14 —OMe —H P15 —OEt —H P16 —OnPr—H P17 —OiPr —H P18 —OcPr —H P19 —OCH₂cPr —H P20 —OCHCF₂ —H P21 —OCF₃ —HP22 —OCH₂CF₃ —H P23 —OCH₂CH₂F —H P24 —OCH₂CH₂OMe —H P25 —OCH₂CH₂NMe₂ —HP26 —F —H P27 —Cl —H P28 —Br —H P29 —I —H P30a —2Py —H P30b —3Py —H P30c—4Py —H P31 —H —Me P32 —Me —Me P33 —Et —Me P34 -nPr —Me P35 -iPr —Me P36-cPr —Me P37 -cBu —Me P38

—Me P39

—Me P40

—Me P41 —CF₃ —Me P42 —CN —Me P43 —Ph —Me P44 —OMe —Me P45 —OEt —Me P46—OnPr —Me P47 —OiPr —Me P48 —OcPr —Me P49 —OCH₂cPr —Me P50 —OCHCF₂ —MeP51 —OCF₃ —Me P52 —OCH₂CF₃ —Me P53 —OCH₂CH₂F —Me P54 —OCH₂CH₂OMe —Me P55—OCH₂CH₂NMe₂ —Me P56 —F —Me P57 —Cl —Me P58 —Br —Me P59 —I —Me P60a —2Py—Me P60b —3Py —Me P60c —4Py —Me P61 —H —Et P62 —Me —Et P63 —Et —Et P64-nPr —Et P65 -iPr —Et P66 -cPr —Et P67 -cBu —Et P68

—Et P69

—Et P70

—Et P71 —CF₃ —Et P72 —CN —Et P73 —Ph —Et P74 —OMe —Et P75 —OEt —Et P76—OnPr —Et P77 —OiPr —Et P78 —OcPr —Et P79 —OCH₂cPr —Et P80 —OCHCF₂ —EtP81 —OCF₃ —Et P82 —OCH₂CF₃ —Et P83 —OCH₂CH₂F —Et P84 —OCH₂CH₂OMe —Et P85—OCH₂CH₂NMe₂ —Et P86 —F —Et P87 —Cl —Et P88 —Br —Et P89 —I —Et P90a —2Py—Et P90b —3Py —Et P90c —4Py —Et

TABLE 200

No —R¹¹ —R¹² Q1 —H -nPr Q2 —Me -nPr Q3 —Et -nPr Q4 -nPr -nPr Q5 -iPr-nPr Q6 -cPr -nPr Q7 -cBu -nPr Q8

-nPr Q9

-nPr Q10

-nPr Q11 —CF₃ -nPr Q12 —CN -nPr Q13 —Ph -nPr Q14 —OMe -nPr Q15 —OEt -nPrQ16 —OnPr -nPr Q17 —OiPr -nPr Q18 —OcPr -nPr Q19 —OCH₂cPr -nPr Q20—OCHCF₂ -nPr Q21 —OCF₃ -nPr Q22 —OCH₂CF₃ -nPr Q23 —OCH₂CH₂F -nPr Q24—OCH₂CH₂OMe -nPr Q25 —OCH₂CH₂NMe₂ -nPr Q26 —F -nPr Q27 —Cl -nPr Q28 —Br-nPr Q29 —I -nPr Q30a —2Py -nPr Q30b —3Py -nPr Q30c —4Py -nPr Q31 —H-iPr Q32 —Me -iPr Q33 —Et -iPr Q34 -nPr -iPr Q35 -iPr -iPr Q36 -cPr -iPrQ37 -cBu -iPr Q38

-iPr Q39

-iPr Q40

-iPr Q41 —CF₃ -iPr Q42 —CN -iPr Q43 —Ph -iPr Q44 —OMe -iPr Q45 —OEt -iPrQ46 —OnPr -iPr Q47 —OiPr -iPr Q48 —OcPr -iPr Q49 —OCH₂cPr -iPr Q50—OCHCF₂ -iPr Q51 —OCF₃ -iPr Q52 —OCH₂CF₃ -iPr Q53 —OCH₂CH₂F -iPr Q54—OCH₂CH₂OMe -iPr Q55 —OCH₂CH₂NMe₂ -iPr Q56 —F -iPr Q57 —Cl -iPr Q58 —Br-iPr Q59 —I -iPr Q60a —2Py -iPr Q60b —3Py -iPr Q60c —4Py -iPr Q61 —H-cPr Q62 —Me -cPr Q63 —Et -cPr Q64 -nPr -cPr Q65 -iPr -cPr Q66 -cPr -cPrQ67 -cBu -cPr Q68

-cPr Q69

-cPr Q70

-cPr Q71 —CF₃ -cPr Q72 —CN -cPr Q73 —Ph -cPr Q74 —OMe -cPr Q75 —OEt -cPrQ76 —OnPr -cPr Q77 —OiPr -cPr Q78 —OcPr -cPr Q79 —OCH₂cPr -cPr Q80—OCHCF₂ -cPr Q81 —OCF₃ -cPr Q82 —OCH₂CF₃ -cPr Q83 —OCH₂CH₂F -cPr Q84—OCH₂CH₂OMe -cPr Q85 —OCH₂CH₂NMe₂ -cPr Q86 —F -cPr Q87 —Cl -cPr Q88 —Br-cPr Q89 —I -cPr Q90a —2Py -cPr Q90b —3Py -cPr Q90c —4Py -cPr

TABLE 201

No —R¹¹ —R¹² R1 —H —Cl R2 —Me —Cl R3 —Et —Cl R4 -nPr —Cl R5 -iPr —Cl R6-cPr —Cl R7 -cBu —Cl R8

—Cl R9

—Cl R10

—Cl R11 —CF₃ —Cl R12 —CN —Cl R13 —Ph —Cl R14 —OMe —Cl R15 —OEt —Cl R16—OnPr —Cl R17 —OiPr —Cl R18 —OcPr —Cl R19 —OCH₂cPr —Cl R20 —OCHCF₂ —ClR21 —OCF₃ —Cl R22 —OCH₂CF₃ —Cl R23 —OCH₂CH₂F —Cl R24 —OCH₂CH₂OMe —Cl R25—OCH₂CH₂NMe₂ —Cl R26 —F —Cl R27 —Cl —Cl R28 —Br —Cl R29 —I —Cl R30a —2Py—Cl R30b —3Py —Cl R30c —4Py —Cl R31 —H —Br R32 —Me —Br R33 —Et —Br R34-nPr —Br R35 -iPr —Br R36 -cPr —Br R37 -cBu —Br R38

—Br R39

—Br R40

—Br R41 —CF₃ —Br R42 —CN —Br R43 —Ph —Br R44 —OMe —Br R45 —OEt —Br R46—OnPr —Br R47 —OiPr —Br R48 —OcPr —Br R49 —OCH₂cPr —Br R50 —OCHCF₂ —BrR51 —OCF₃ —Br R52 —OCH₂CF₃ —Br R53 —OCH₂CH₂F —Br R54 —OCH₂CH₂OMe —Br R55—OCH₂CH₂NMe₂ —Br R56 —F —Br R57 —Cl —Br R58 —Br —Br R59 —I —Br R60a —2Py—Br R60b —3Py —Br R60c —4Py —Br R61 —H —I R62 —Me —I R63 —Et —I R64 -nPr—I R65 -iPr —I R66 -cPr —I R67 -cBu —I R68

—I R69

—I R70

—I R71 —CF₃ —I R72 —CN —I R73 —Ph —I R74 —OMe —I R75 —OEt —I R76 —OnPr—I R77 —OiPr —I R78 —OcPr —I R79 —OCH₂cPr —I R80 —OCHCF₂ —I R81 —OCF₃ —IR82 —OCH₂CF₃ —I R83 —OCH₂CH₂F —I R84 —OCH₂CH₂OMe —I R85 —OCH₂CH₂NMe₂ —IR86 —F —I R87 —Cl —I R88 —Br —I R89 —I —I R90a —2Py —I R90b —3Py —I R90c—4Py —I

INDUSTRIAL APPLICABILITY

The compound of formula (I) or a salt thereof has inhibitory activityagainst the kinase activity of EML4-ALK fusion protein, as well asgrowth inhibitory activity against EML4-ALK fusion protein-dependentcells, and can be used as an active ingredient in pharmaceuticalcompositions for preventing and/or treating cancer, such as lung cancerin one embodiment, non-small cell lung cancer or small cell lung cancerin another embodiment, ALK fusion polynucleotide-positive cancer in yetanother embodiment, ALK fusion polynucleotide-positive lung cancer inyet another embodiment, ALK fusion polynucleotide-positive non-smallcell lung cancer in yet another embodiment, ALK fusion protein-positivecancer in yet another embodiment, ALK fusion protein-positive lungcancer in yet another embodiment, ALK fusion protein-positive non-smallcell lung cancer in yet another embodiment, EML4-ALK fusionpolynucleotide-positive cancer in yet another embodiment, EML4-ALKfusion polynucleotide-positive lung cancer in yet another embodiment,EML4-ALK fusion polynucleotide-positive non-small cell lung cancer inyet another embodiment, EML4-ALK fusion protein-positive cancer in yetanother embodiment, EML4-ALK fusion protein-positive lung cancer in yetanother embodiment, or EML4-ALK fusion protein-positive non-small celllung cancer in yet another embodiment.

The invention claimed is:
 1. A compound of formula (I) or a saltthereof:

wherein the symbols are as defined below: —X— is a group of formula(II):

A is chloro, ethyl, or isopropyl; R¹ is phenyl in which the carbon atthe 4-position is substituted with —W—Y—Z and the carbon at the3-position may be substituted with a group selected from the groupconsisting of halogen, R⁰⁰, and —O—R⁰⁰; R⁰⁰ is lower alkyl which may besubstituted with one or more halogens; —W— is a bond,piperidine-1,4-diyl, or piperazine-1,4-diyl; —Y— is a bond; Z is anon-aromatic heterocyclic ring which may be substituted with one or moreR⁰⁰; R² is (i) cycloalkyl which may be substituted with one or moregroups selected from the group consisting of —N(lower alkyl)₂, loweralkyl, —COO-lower alkyl, —OH, —COOH, —CONH—R^(ZB), and morpholinyl, or(ii) a non-aromatic heterocyclic ring which may be substituted with oneor more groups selected from the group consisting of lower alkyl,—CO-lower alkyl, oxo, —CO—R^(ZB), and benzyl; R^(ZB) is phenyl which maybe substituted with a group selected from the group consisting ofhalogen and —O-lower alkyl; and R³ is —H.
 2. The compound according toclaim 1 or a salt thereof, wherein R¹ is phenyl in which the carbon atthe 4-position is substituted with a group selected from the groupconsisting of 4-(4-methylpiperazin-1-yl)piperidin-1-yl,4-(1-methylpiperidin-4-yl)piperazin-1-yl, 4-methylpiperazin-1-yl, and4-isopropylpiperazin-1-yl, and the carbon at the 3-position may besubstituted with a group selected from the group consisting of fluoro,methyl, trifluoromethyl, and methoxy.
 3. The compound according to claim1 or a salt thereof, wherein R² is 4-hydroxycyclohexyl,4-hydroxy-4-methylcyclohexyl, or tetrahydropyran-4-yl.
 4. The compoundaccording to claim 1 or a salt thereof, wherein said compound is:6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide,6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide,6-ethyl-5-[(cis-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,6-ethyl-5-[(trans-4-hydroxycyclohexyl)amino]-3-{[4-(4-isopropylpiperazin-1-yl)-3-methylphenyl]amino}pyrazine-2-carboxamide,6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,6-chloro-5-[(trans-4-hydroxycyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide,6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,6-ethyl-3-{[3-fluoro-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,6-isopropyl-3-{[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide,or6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide.5. A pharmaceutical composition, which comprises the compound accordingto claim 1 or a salt thereof and a pharmaceutically acceptableexcipient.
 6. An inhibitor against the kinase activity of EML4-ALKfusion protein, which comprises the compound according to claim 1 or asalt thereof.
 7. A pharmaceutical composition for preventing or treatingcancer, lung cancer, non-small cell lung cancer, small cell lung cancer,EML4-ALK fusion polynucleotide-positive cancer, EML4-ALK fusionpolynucleotide-positive lung cancer, or EML4-ALK fusionpolynucleotide-positive non-small cell lung cancer, which comprises thecompound according to claim 1 or a salt thereof.
 8. The compoundaccording to claim 1 or a salt thereof, wherein said compound is:5-[(trans-4-hydroxycyclohexyl)amino]-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(trifluoromethyl)phenyl}amino)pyrazine-2-carboxamide.9. The compound according to claim 1 or a salt thereof, wherein saidcompound is:6-ethyl-5-[(trans-4-hydroxy-4-methylcyclohexyl)amino]-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide.10. The compound according to claim 1 or a salt thereof, wherein saidcompound is:6-ethyl-3-({3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide.11. The compound according to claim 1 or a salt thereof, wherein saidcompound is:6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide.12. The compound according to claim 1 or a salt thereof, wherein saidcompound is:6-ethyl-3-({3-methyl-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]phenyl}amino)-5-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide.